1,2,4-TRIAZOLO[4,3-a]PYRIDINE COMPOUNDS AND THEIR USE AS POSITIVE ALLOSTERIC MODULATORS OF MGLUR2 RECEPTORS

ABSTRACT

The present invention relates to novel 1,2,4-triazolo[4,3-a]pyridine compounds as positive allosteric modulators (PAMs) of the metabotropic glutamate receptor subtype 2 (“mGluR2”). The invention is also directed to pharmaceutical compositions comprising such compounds, to processes for preparing such compounds and compositions, and to the use of such compounds and compositions for the prevention or treatment of disorders in which mGluR2 subtype of metabotropic receptors is involved.

FIELD OF THE INVENTION

The present invention relates to novel 1,2,4-triazolo[4,3-a]pyridinecompounds as positive allosteric modulators (PAMs) of the metabotropicglutamate receptor subtype 2 (“mGluR2”). The invention is also directedto pharmaceutical compositions comprising such compounds, to processesfor preparing such compounds and compositions, and to the use of suchcompounds and compositions for the prevention or treatment of disordersin which mGluR2 subtype of metabotropic receptors is involved.

BACKGROUND OF THE INVENTION

Glutamate is the major amino acid neurotransmitter in the mammaliancentral nervous system. Glutamate plays a major role in numerousphysiological functions, such as learning and memory but also sensoryperception, development of synaptic plasticity, motor control,respiration, and regulation of cardiovascular function. Furthermore,glutamate is at the centre of several different neurological andpsychiatric diseases, where there is an imbalance in glutamatergicneurotransmission.

Glutamate mediates synaptic neurotransmission through the activation ofionotropic glutamate receptor channels (iGluRs), and the NMDA, AMPA andkainate receptors which are responsible for fast excitatorytransmission.

In addition, glutamate activates metabotropic glutamate receptors(mGluRs) which have a more modulatory role that contributes to thefine-tuning of synaptic efficacy.

Glutamate activates the mGluRs through binding to the largeextracellular amino-terminal domain of the receptor, herein called theorthosteric binding site. This binding induces a conformational changein the receptor which results in the activation of the G-protein andintracellular signaling pathways.

The mGluR2 subtype is negatively coupled to adenylate cyclase viaactivation of Gαi-protein, and its activation leads to inhibition ofglutamate release in the synapse. In the central nervous system (CNS),mGlu2 receptors are abundant mainly throughout cortex, thalamic regions,accessory olfactory bulb, hippocampus, amygdala, caudate-putamen andnucleus accumbens.

Activating mGluR2 was shown in clinical trials to be efficacious totreat anxiety disorders (for studies with orthosteric mGlu2/3 agonists,see Michelson et al. Neuropharmacology 2005, 49(S1), 84-257; Dunayevichet al. Neuropsychopharmacology 2008, 33(7), 1603-10), LY354740 had beenpreviously evaluated in non-clinical and clinical model systemspredicting utility in the treatment of anxiety disorders beyondgeneralized anxiety depression (GAD), e.g. panic (see Dunayevich et al.2008). Non-clinical studies, suggest a role for both mGlu2 and mGlu3receptors in anxiolysis (Linden et al. Neuropharmacology 2005, 49,120-134) whilst it has been suggested that positive allostericmodulation of the mGluR2 may be sufficient for an anxiolytic effect(Johnson et al. Psychopharmacology (Berl) 2005, 179(1), 271-283).

In addition, activating mGluR2 was shown to be potentially efficaciousfor the treatment of(a) schizophrenia (Patil et al. Nat Med 2007, 13(9), 1102-7); laterstudies however, do not support treatment of acute exacerbations ofschizophrenia with an mGluR2 agonist or allosteric modulator (Adams etal. BMC Psychiatry 2013, 13(1), 143; Kinon et al. J ClinPsychopharmacol. 2013, 31(3), 349-55; Litman et al. (2013) NCDEU Meeting(abstract)) but do not exclude application for other specific symptomclusters (e.g. negative symptoms (Kent et al. “Safety, tolerability andpotential therapeutic efficacy of a novel glutamate modulator asadjunctive treatment in patients with schizophrenia” abstract No. 3160and poster NR10-47, American Psychiatric Association 166th AnnualMeeting 2013 (APA 2013), May 18-22, 2013, San Francisco, Calif., USA))or for other phases in the disease (e.g. residual symptoms);(b) epilepsy, based on acute non-clinical studies with mixed mGlu2/3receptor agonists (Moldrich et al. Eur J Pharmacol. 2003, 476, 3-16;Barton et al. Epilepsy Research 2003, 56, 17-26); continuedadministration of an mGlu2/3 agonist paradoxically induced seizureactivity in long-term toxicology studies (Dunayevich et al. (2008), thisparadoxical effect may be related to agonist-induced changes in thesensitivity of the receptor systems (tachyphylaxis); positive allostericmodulators, in contrast, modulate ongoing neurotransmission but are notdirectly stimulatory, thereby reducing the risk for tachyphylaxis;(c) drug addiction/dependence (Barrett, Neuropsychopharmacology 2010,35, 2007-2008; Foster, Curr Drug Abuse Rev 2009, 2, 83-98);(d) Parkinson's disease (see for example Johnson et al. CNS NeurolDisord Drug Targets 2009, 8, 475-491; Konieczny et al. NaunynSchmiedebergs Arch. Pharmacol. 1998, 358 (4), 500-502);(e) pain (Chiechio and Nicoletti, Curr Opin Pharmacol 2012, 12, 28-34;Jones et al. Neuropharmacology 2005, 49, 206-218; Neugebauer, [Review]Pain 2002, 98 (1-2), 1-8; Simmons et al. Pharmacology, Biochemistry andBehavior 2002, 73, 419-427);(f) sleep disorders (Ahnaou et al. European Journal of Pharmacology2009, 603, 62-72);(f) Huntington's disease (based on a potential disease modifying effect(Schiefer et al. Brain Res 2004, 1019, 246-254) which is to be confirmedfurther); and(g) depression (although no efficacy signal was detected on the primaryoutcome measure, adjunctive administration of JNJ-40411813/ADX71149 inthe dose range tested in a multicenter, double-blind, placebo-controlledstudy in adults with major depressive disorder with anxiety symptomsshowed efficacy signals on several secondary outcome measures of bothdepression and anxiety (Kent et al. “Efficacy and Safety of a NovelmGlu2 Receptor Positive Allosteric Modulator as an Adjunctive Treatmentto an SSRI/SNRT in the Treatment of Anxious Depression”, Abstract toposter and oral presentation, American Society of ClinicalPsychopharmacology (ASCP) 2014 Annual Meeting, Jun. 16-19, 2014 WestinDiplomat, Hollywood, Fla.)).

A new avenue for developing selective compounds acting at mGluRs is toidentify compounds that act through allosteric mechanisms, modulatingthe receptor by binding to a site different from the highly conservedorthosteric binding site.

Positive allosteric modulators of mGluRs have emerged recently as novelpharmacological entities offering this attractive alternative.

It was demonstrated that such compounds do not activate the receptor bythemselves. Rather, they enable the receptor to produce an increasedresponse to a concentration of glutamate, which by itself induces aminimal response. Mutational analysis has demonstrated unequivocallythat the binding of mGluR2 positive allosteric modulators does not occurat the orthosteric site, but instead at an allosteric site situatedwithin the seven transmembrane region of the receptor.

Animal data suggest that positive allosteric modulators of mGluR2 haveeffects in anxiety and psychosis models similar to those obtained withorthosteric agonists. Allosteric modulators of mGluR2 were shown to beactive in fear-potentiated startle (Johnson et al. J Med Chem 2003, 46,3189-3192; Johnson et al. Psychopharmacology 2005, 179, 271-283), and instress-induced hyperthermia models of anxiety (Johnson et al. 2005).Furthermore, such compounds were shown to be active in reversal ofketamine—(Govek et al. Bioorg Med Chem Lett 2005, 15(18), 4058-4072) oramphetamine—(Galici et al. J Pharm Exp Ther 2005, 315(3), 1181-1187)induced hyperlocomotion, and in reversal of amphetamine-induceddisruption of prepulse inhibition of the acoustic startle effect (Galiciet al. 2005) models of schizophrenia.

JNJ-40411813/ADX71149, an mGlu2 PAM (which in rat also displays5-HT_(2A) antagonism activity due to a rat-specific metabolite) hasundergone clinical trials for the treatment of schizophrenia, andanxiety-depression (see for instance www. Clinicaltrials.gov).Non-clinical data in the lactate-induced panic model in rodents suggeststhat it could have potential in the treatment of further anxietydisorders such as panic disorder and phobias, such as agoraphobia(Shekhar et al. Neuropsychopharmacology 2013, 38, S435-S593 (W220).JNJ-40411813 was also observed to reduce craving and improve smokingcessation-induced deficits in attention and episodic memory versusplacebo (Salih et al. Journal of Psychopharmacology, submitted) andshowed an efficacy signal in S-ketamine-induced negative symptoms inhealthy volunteers and patients with predominant negative symptoms ofschizophrenia (De Boer et al. Society of Biological Psychiatry 68^(th)Annual Scientific Convention of Society of Biological Psychiatry, May16-18, 2013, Hilton Union Square, San Francisco, Calif., Abstract2013-P-1060-SOBP).

Positive allosteric modulators enable potentiation of the glutamateresponse, but they have also been shown to potentiate the response toorthosteric mGluR2 agonists such as LY379268 or DCG-IV. These dataprovide evidence for yet another novel therapeutic approach to treat theabove mentioned neurological and psychiatric diseases involving mGluR2,which would use a combination of a positive allosteric modulator ofmGluR2 together with an orthosteric agonist of mGluR2.

Various compounds have been described as mGluR2 positive allostericmodulators. WO2010/130424, WO2010/130423, WO2010/130422, andWO2012/062750, WO2012/062751, and WO2012/062759, published on 18 Nov.2010 and 18 May 2012, respectively, disclose1,2,4-triazolo[4,3-a]pyridine derivatives as mGluR2 positive allostericmodulators.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to potent mGluR2 PAM compounds with anadvantageous balance of properties. Thus, the present invention isdirected to 1,2,4-triazolo[4,3-a]pyridine derivatives of Formula (I)

and the stereochemically isomeric forms thereof, whereinR¹ is selected from the group consisting of C₁₋₆alkyl,(C₃₋₈cycloalkyl)C₁₋₃alkyl, and (C₁₋₃alkyl;each R² is independently selected from F, Cl, C₁₋₃alkyl, C₁₋₃alkyloxy,mono- or polyhaloC₁₋₃alkyl, and mono- or polyhaloC₁₋₃alkyloxy;n is an integer selected from 1, 2, and 3;and the pharmaceutically acceptable salts and the solvates thereof.The present invention also relates to a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of Formula(I) and a pharmaceutically acceptable carrier or excipient.Additionally, the invention relates to a compound of Formula (I) for useas a medicament and to a compound of Formula (I) for use as a medicamentfor the treatment or prevention of neurological and psychiatricdisorders in which mGluR2 is involved.The invention also relates to the use of a compound according to Formula(I) or a pharmaceutical composition according to the invention for themanufacture of a medicament for treating or preventing neurological andpsychiatric disorders in which mGluR2 is involved.Additionally, the invention relates to the use of a compound of Formula(I) in combination with an additional pharmaceutical agent for themanufacture of a medicament for treating or preventing neurological andpsychiatric disorders in which mGluR2 is involved.Furthermore, the invention relates to a process for preparing apharmaceutical composition according to the invention, characterized inthat a pharmaceutically acceptable carrier is intimately mixed with atherapeutically effective amount of a compound of Formula (I).The invention also relates to a product comprising a compound of Formula(I) and an additional pharmaceutical agent, as a combined preparationfor simultaneous, separate or sequential use in the treatment orprevention of neurological or psychiatric disorders and diseases.The present invention relates in particular to compounds of Formula (I)as defined hereinabove, and stereoisomeric forms thereof, whereinR¹ is selected from the group consisting of CH₃CH₂, CH₃CH₂CH₂,(cyclopropyl)methyl, (cyclobutyl)methyl, ethyloxymethyl andmethyloxymethyl; and the rest of variables are as defined herein; andthe pharmaceutically acceptable salts and the solvates thereof.In a further embodiment, the present invention relates to compounds ofFormula (I) as defined hereinabove, and stereoisomeric forms thereof,whereinR¹ is selected from the group consisting of CH₃CH₂, (cyclopropyl)methyl,(cyclobutyl)methyl and methyloxymethyl; and the rest of variables are asdefined herein; and the pharmaceutically acceptable salts and thesolvates thereof.In a further embodiment, the present invention relates to compounds ofFormula (I) as defined hereinabove, and stereoisomeric forms thereof,whereinR¹ is selected from the group consisting of CH₃CH₂, (cyclopropyl)methyl,(cyclobutyl)methyl and ethyloxymethyl; and the rest of variables are asdefined herein; and the pharmaceutically acceptable salts and thesolvates thereof.In an additional embodiment, the invention relates to a compound ofFormula (I) as defined hereinabove, and stereoisomeric forms thereofwhereineach R² is independently selected from F, Cl, CH₃, CH₃O and CF₃; and thepharmaceutically acceptable salts and the solvates thereof.In a further embodiment, the present invention relates to compounds ofFormula (I) as defined herein having the Formula (Ia)

wherein the variables are as defined in Formula (I) herein, and thepharmaceutically acceptable salts and the solvates thereof.In a further embodiment, the present invention relates to compounds ofFormula (I) as defined herein having the Formula (Ib)

wherein the variables are as defined in Formula (I) herein, and thepharmaceutically acceptable salts and the solvates thereof.Particular compounds may be selected from the group of

-   3-(Cyclopropylmethyl)-7-[1-(4-fluorophenoxy)ethyl]-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine;-   3-(Cyclopropylmethyl)-7-[(1*R)-1-(4-fluorophenoxy)ethyl]-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine;-   3-(Cyclopropylmethyl)-7-[(1*S)-1-(4-fluorophenoxy)ethyl]-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine;-   3-(Cyclopropylmethyl)-7-[(1S)-1-(2,4-difluorophenoxy)ethyl]-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine;-   3-(Cyclopropylmethyl)-7-[(1R)-1-(2,4-difluorophenoxy)ethyl]-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine;-   3-(Cyclopropylmethyl)-7-[1-(2,4-difluorophenoxy)ethyl]-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine;-   3-(Cyclopropylmethyl)-7-[(1S)-1-(3,5-difluorophenoxy)ethyl]-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine;-   3-(Cyclopropylmethyl)-7-[(1S)-1-(3,4-difluorophenoxy)ethyl]-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine;-   3-(Cyclopropylmethyl)-7-[(1S)-1-(2,3-difluorophenoxy)ethyl]-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine;-   3-(Cyclopropylmethyl)-7-[(1S)-1-(2,5-difluorophenoxy)ethyl]-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine;-   3-(Cyclopropylmethyl)-7-[(1S)-1-(2,6-difluorophenoxy)ethyl]-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine;-   3-(Cyclopropylmethyl)-7-[(1S)-1-(4-fluoro-2-methoxyphenoxy)ethyl]-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine;-   3-(Cyclobutylmethyl)-7-[1-(2,4-difluorophenoxy)ethyl]-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine;-   7-[(1S)-1-(2-Chloro-4-methylphenoxy)ethyl]-3-(cyclopropylmethyl)-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine;-   3-(Cyclopropylmethyl)-7-[(1    S)-1-(4-fluoro-2-methylphenoxy)ethyl]-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine;-   3-(Cyclopropylmethyl)-8-(trifluoromethyl)-7-[(1S)-1-(2,4,6-trifluorophenoxy)ethyl][1,2,4]triazolo[4,3-a]pyridine;-   7-[1-(2,4-Difluorophenoxy)ethyl]-3-(ethoxymethyl)-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine;-   3-Ethyl-8-(trifluoromethyl)-7-[1-(2,4,6-trifluorophenoxy)ethyl][1,2,4]triazolo[4,3-a]pyridine;-   7-[1-(2,4-Difluorophenoxy)ethyl]-3-ethyl-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine;-   3-(Cyclobutylmethyl)-7-[(1*R)-1-(2,4-difluorophenoxy)ethyl]-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine;-   3-(Cyclobutylmethyl)-7-[(1*S)-1-(2,4-difluorophenoxy)ethyl]-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine;-   3-(Ethoxymethyl)-8-(trifluoromethyl)-7-[(1*R)-1-(2,4,6-trifluorophenoxy)ethyl][1,2,4]triazolo[4,3-a]pyridine;-   3-(Ethoxymethyl)-8-(trifluoromethyl)-7-[(1*S)-1-(2,4,6-trifluorophenoxy)ethyl][1,2,4]triazolo[4,3-a]pyridine;-   7-[(1*S)-1-(2,4-Difluorophenoxy)ethyl]-3-(ethoxymethyl)-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine;-   7-[(1*R)-1-(2,4-Difluorophenoxy)ethyl]-3-(ethoxymethyl)-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine;-   7-[(1*R)-1-(2,4-Difluorophenoxy)ethyl]-3-ethyl-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine;-   7-[(1*S)-1-(2,4-Difluorophenoxy)ethyl]-3-ethyl-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine;-   7-[1-(2,4-Difluorophenoxy)ethyl]-3-propyl-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine;-   3-Ethyl-8-(trifluoromethyl)-7-[(1*R)-1-(2,4,6-trifluorophenoxy)ethyl]-[1,2,4]triazolo[4,3-a]pyridine;-   3-Ethyl-8-(trifluoromethyl)-7-[(1*S)-1-(2,4,6-trifluorophenoxy)ethyl]-[1,2,4]triazolo[4,3-a]pyridine;-   7-[(1*R)-(2,4-difluorophenoxy)ethyl]-3-propyl-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine;    and-   7-[(1*S)-(2,4-difluorophenoxy)ethyl]-3-propyl-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine.

Included within the scope of this list are stereoisomeric forms, thepharmaceutically acceptable salts and the solvates thereof.

In an additional embodiment, the compound may be selected from3-(Cyclopropylmethyl)-7-[(1S)-1-(2,4-difluorophenoxy)ethyl]-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridinehydrochloride salt.

The names of the compounds of the present invention were generatedaccording to the nomenclature rules agreed upon by the ChemicalAbstracts Service (C.A.S.) using Advanced Chemical Development, Inc.,software (ACD/Name product version 10.01.0.14105, October 2006). In caseof tautomeric forms, the name of the depicted tautomeric form of thestructure was generated. However it should be clear that the othernon-depicted tautomeric form is also included within the scope of thepresent invention.

DEFINITIONS

The notation “C₁₋₃alkyl” or “C₁₋₆alkyl” as used herein alone or as partof another group, defines a saturated, straight or branched, hydrocarbonradical having, unless otherwise stated, from 1 to 3 or 1 to 6 carbonatoms, such as methyl, ethyl, 1-propyl, 1-methylethyl, butyl,1-methyl-propyl, 2-methyl-1-propyl, 1,1-dimethylethyl, 3-methyl-1-butyl,1-pentyl, 1-hexyl and the like.The notation “C₃₋₈cycloalkyl” as used herein alone or as part of anothergroup, defines a saturated, cyclic hydrocarbon radical having from 3 to8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl and cyclooctyl.The notation “halogen” or “halo” as used herein alone or as part ofanother group, refers to fluoro, chloro, bromo or iodo, with fluoro orchloro being preferred.The notation “mono- and polyhaloC₁₋₃alkyl” as used herein alone or aspart of another group, refers to C₁₋₃alkyl as defined before,substituted with 1, 2, 3 or where possible with more halo atoms asdefined before.Whenever the term “substituted” is used in the present invention, it ismeant, unless otherwise is indicated or is clear from the context, toindicate that one or more hydrogens, preferably from 1 to 3 hydrogens,more preferably from 1 to 2 hydrogens, more preferably 1 hydrogen, onthe atom or radical indicated in the expression using “substituted” arereplaced with a selection from the indicated group, provided that thenormal valency is not exceeded, and that the substitution results in achemically stable compound, i.e. a compound that is sufficiently robustto survive isolation to a useful degree of purity from a reactionmixture, and formulation into a therapeutic agent.The term “subject” as used herein, refers to an animal, preferably amammal, most preferably a human, who is or has been the object oftreatment, observation or experiment.The term “therapeutically effective amount” as used herein, means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician, which includes alleviation of the symptoms of thedisease or disorder being treated.As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombinations of the specified ingredients in the specified amounts.It will be appreciated that some of the compounds of Formula (I) andtheir pharmaceutically acceptable addition salts and solvates thereofmay contain one or more centres of chirality and exist as stereoisomericforms.The term “compounds of the invention” as used herein, is meant toinclude the compounds of Formula (I), and the salts and solvatesthereof.As used herein, any chemical formula with bonds shown only as solidlines and not as solid wedged or hashed wedged bonds, or otherwiseindicated as having a particular configuration (e.g. R, S) around one ormore atoms, contemplates each possible stereoisomer, or mixture of twoor more stereoisomers.Hereinbefore and hereinafter, the term “compound of Formula (I)” ismeant to include the stereoisomers thereof and the tautomeric formsthereof.The terms “stereoisomers”, “stereoisomeric forms” or “stereochemicallyisomeric forms” hereinbefore or hereinafter are used interchangeably.The invention includes all stereoisomers of the compounds of theinvention either as a pure stereoisomer or as a mixture of two or morestereoisomers.Enantiomers are stereoisomers that are non-superimposable mirror imagesof each other. A 1:1 mixture of a pair of enantiomers is a racemate orracemic mixture. Diastereomers (or diastereoisomers) are stereoisomersthat are not enantiomers, i.e. they are not related as mirror images. Ifa compound contains a double bond, the substituents may be in the E orthe Z configuration. Substituents on bivalent cyclic (partially)saturated radicals may have either the cis- or trans-configuration; forexample if a compound contains a disubstituted cycloalkyl group, thesubstituents may be in the cis or trans configuration.Therefore, the invention includes enantiomers, diastereomers, racemates,E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof,whenever chemically possible.The meaning of all those terms, i.e. enantiomers, diastereomers,racemates, E isomers, Z isomers, cis isomers, trans isomers and mixturesthereof are known to the skilled person.The absolute configuration is specified according to theCahn-Ingold-Prelog system. The configuration at an asymmetric atom isspecified by either R or S. Resolved stereoisomers whose absoluteconfiguration is not known can be designated by (+) or (−) depending onthe direction in which they rotate plane polarized light. For instance,resolved enantiomers whose absolute configuration is not known can bedesignated by (+) or (−) depending on the direction in which they rotateplane polarized light.When a specific stereoisomer is identified, this means that saidstereoisomer is substantially free, i.e. associated with less than 50%,preferably less than 20%, more preferably less than 10%, even morepreferably less than 5%, in particular less than 2% and most preferablyless than 1%, of the other isomers. Thus, when a compound of Formula (I)is for instance specified as (R), this means that the compound issubstantially free of the (S) isomer; when a compound of Formula (I) isfor instance specified as E, this means that the compound issubstantially free of the Z isomer; when a compound of Formula (I) isfor instance specified as cis, this means that the compound issubstantially free of the trans isomer.Some of the compounds according to Formula (I) may also exist in theirtautomeric form. Such forms in so far as they may exist, although notexplicitly indicated in the above formula are intended to be includedwithin the scope of the present invention. It follows that a singlecompound may exist in both stereoisomeric and tautomeric forms.For therapeutic use, salts of the compounds of Formula (I) are thosewherein the counterion is pharmaceutically acceptable. However, salts ofacids and bases which are non-pharmaceutically acceptable may also finduse, for example, in the preparation or purification of apharmaceutically acceptable compound. All salts, whetherpharmaceutically acceptable or not, are included within the ambit of thepresent invention.The pharmaceutically acceptable acid and base addition salts asmentioned hereinabove or hereinafter are meant to comprise thetherapeutically active non-toxic acid and base addition salt forms whichthe compounds of Formula (I) are able to form. The pharmaceuticallyacceptable acid addition salts can conveniently be obtained by treatingthe base form with such appropriate acid. Appropriate acids comprise,for example, inorganic acids such as hydrohalic acids, e.g. hydrochloricor hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; ororganic acids such as, for example, acetic, propanoic, hydroxyacetic,lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e.butanedioic acid), maleic, fumaric, malic, tartaric, citric,methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic,cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.Conversely said salt forms can be converted by treatment with anappropriate base into the free base form.The compounds of Formula (I) containing an acidic proton may also beconverted into their non-toxic metal or amine addition salt forms bytreatment with appropriate organic and inorganic bases. Appropriate basesalt forms comprise, for example, the ammonium salts, the alkali andearth alkaline metal salts, e.g. the lithium, sodium, potassium,magnesium, calcium salts and the like, salts with organic bases, e.g.primary, secondary and tertiary aliphatic and aromatic amines such asmethylamine, ethylamine, propylamine, isopropylamine, the fourbutylamine isomers, dimethylamine, diethylamine, diethanolamine,dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine,piperidine, morpholine, trimethylamine, triethylamine, tripropylamine,quinuclidine, pyridine, quinoline and isoquinoline; the benzathine,N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids suchas, for example, arginine, lysine and the like. Conversely the salt formcan be converted by treatment with acid into the free acid form.The term solvate comprises the solvent addition forms as well as thesalts thereof, which the compounds of Formula (I) are able to form.Examples of such solvent addition forms are e.g. hydrates, alcoholatesand the like.In the framework of this application, an element, in particular whenmentioned in relation to a compound according to Formula (I), comprisesall isotopes and isotopic mixtures of this element, either naturallyoccurring or synthetically produced, either with natural abundance or inan isotopically enriched form. Radiolabelled compounds of Formula (I)may comprise a radioactive isotope selected from the group of ³H, ¹¹C,¹⁸F, ¹²²I, ¹²³I, ¹²⁵I, ¹³¹I, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br and ⁸²Br. Preferably, theradioactive isotope is selected from the group of ³H, ¹¹C and ¹⁸F.

Preparation

The compounds according to the invention can generally be prepared by asuccession of steps, each of which is known to the skilled person. Inparticular, the compounds can be prepared according to the followingsynthesis methods.

The compounds of Formula (I) may be synthesized in the form of racemicmixtures of enantiomers which can be separated from one anotherfollowing art-known resolution procedures. The racemic compounds ofFormula (I) may be converted into the corresponding diastereomeric saltforms by reaction with a suitable chiral acid. Said diastereomeric saltforms are subsequently separated, for example, by selective orfractional crystallization and the enantiomers are liberated therefromby alkali. An alternative manner of separating the enantiomeric forms ofthe compounds of Formula (I) involves liquid chromatography orsupercritical fluid chromatography (SFC) using a chiral stationaryphase. Said pure stereochemically isomeric forms may also be derivedfrom the corresponding pure stereochemically isomeric forms of theappropriate starting materials, provided that the reaction occursstereospecifically.

A. Preparation of the Final Compounds

Final compounds according to Formula (I), can be prepared by reacting anintermediate compound of Formula (II) with a compound of Formula (III)according to reaction scheme (1), a reaction that is performed underclassical Mitsunobu conditions. The reaction is preferably conductedwith a phosphine and an azodicarboxylic ester or amide intetrahydrofuran, 1,4-dioxane, diethyl ether, toluene, benzene,dichloromethane, or mixtures thereof, at −30 to 150° C., under thermalheating or microwave irradiation. Phosphines often used aretriphenylphosphine and tributylphosphine which are usually combined withdimethyl azodicarboxylate, diethyl azodicarboxylate, diisopropylazodicarboxylate, di-(4-chlorobenzyl) azodicarboxylate, dibenzylazodicarboxylate, di-tert-butyl azodicarboxylate, azodicarboxylic acidbis-(dimethylamide), azodicarboxylic acid dipiperidide, orazodicarboxylic acid dimorpholide. In reaction scheme (1), all variablesare as defined in Formula (I)

B. Preparation of the Intermediates Experimental Procedure 2

Intermediate compounds according to Formula (II) can be prepared bysubjecting an intermediate of Formula (IV) to conditions that are knownto those skilled in the art. This is illustrated in reaction scheme (2)wherein all variables are defined as mentioned hereabove. Methodsaccomplishing these transformations are well known to those skilled inthe art. Treatment of the aldehyde of formula (IV) with anorganometallic such as methyl lithium or methyl magnesium bromide givesa compound of formula (II). A suitable solvent for this reaction is anether such as tetrahydrofuran and the reaction is usually carried out ata temperature between −78° C. and 40° C. In reaction scheme (2), allvariables are defined as in Formula (I).

Experimental Procedure 3

Intermediate compounds according to Formula (IV) can be prepared byreacting an intermediate of Formula (V) under dihydroxylation andoxidative cleavage conditions that are known to those skilled in the artand can be realized for example with oxone, osmium tetroxide. Theprocess may be carried out optionally in a solvent such as 1,4-dioxane,water and generally at temperatures between about −100° C. and about100° C. A summary of such methods is found in “Comprehensive OrganicTransformations”, VCH Publishers, (1989), R. C. Larock, pp. 595-596.This is illustrated in reaction scheme (3) wherein all variables aredefined as mentioned hereabove.

Experimental Procedure 4

Intermediate compounds according to Formula (V) can be prepared bycoupling reactions, such as Stille or Suzuki reactions of anintermediate of Formula (VI) with a compound of Formula (VII) underconditions that are known to those skilled in the art. The process maybe carried out optionally in a solvent such as 1,4-dioxane, water andgenerally at temperatures between about r.t and about 200° C. in thepresence of a base. This is illustrated in reaction scheme (4) whereinall variables are defined as mentioned hereabove, wherein M istrialkyltin, boronic acid or boronate ester, and a palladium catalystand halo is chloro, bromo or iodo.

Experimental Procedure 5

Intermediate compounds according to Formula (VI) can be preparedfollowing art known procedures by cyclization of an intermediatecompound of Formula (VIII) in the presence of a halogenating agent suchas for example phosphorus (V) oxychloride (POCl₃) in a suitable solventsuch as, for example, dichloroethane, stirred under microwaveirradiation, for a suitable period of time that allows the completion ofthe reaction, as for example 5 min at a temperature between 140-200° C.In reaction scheme (5), R¹ is defined as in Formula (I) and halo ischloro, bromo or iodo.

Experimental Procedure 6

Intermediate compounds according to Formula (VIII) can be prepared byart known procedures by reaction of a hydrazine intermediate of Formula(IX) with acid halides of Formula (X). The reaction can be carried outusing an inert-solvent, such as for example DCM, in the presence of abase such as for example triethylamine, for example at r.t. for asuitable period of time that allows completion of the reaction, forexample 20 min. In reaction scheme (6), R¹ is defined as in Formula (I).

Experimental Procedure 7

Intermediate compounds according to Formula (IX) can be prepared byreacting an intermediate compound of Formula (XI) with hydrazineaccording to reaction scheme (7), a reaction that is performed in asuitable reaction-inert solvent, such as, for example, ethanol, THF or1,4-dioxane under thermal conditions such as, for example, heating thereaction mixture for example at 160° C. under microwave irradiation for30 min or classical thermal heating at 70° C. for 16 h. In reactionscheme (7), halo is chloro, bromo or iodo.

Experimental Procedure 8

Intermediate compounds according to Formula (XI) can be prepared byreacting an intermediate compound of Formula (XII) with benzyl alcoholaccording to reaction scheme (8), a reaction that is performed in asuitable reaction-inert solvent, such as, for example,N,N-dimethylformamide in the presence of a suitable base, such as forexample sodium hydride at r.t. for a suitable period of time that allowsthe completion of the reaction, such as for example 1 h. In reactionscheme (8), halo is chloro, bromo or iodo.

Experimental Procedure 9

Intermediate compounds of Formula (XII), can be prepared by reacting anintermediate of Formula (XIII), with a suitable trifluoromethylatingagent, such as for example fluorosulfonyl(difluoro)acetic acid methylester, according to reaction scheme (9). This reaction is performed in asuitable reaction-inert solvent such as, for example,N,N-dimethylformamide in the presence of a suitable coupling agent suchas for example, copper(I) iodide, under thermal conditions such as, forexample, heating the reaction mixture for example at 160° C. undermicrowave irradiation for 45 min. In reaction scheme (9), halo ischloro, bromo or iodo.

The starting materials according to Formulae (II), (VII) (X) or (XIII)are compounds that are either commercially available or may be preparedaccording to conventional reaction procedures generally known to thoseskilled in the art.

Pharmacology

The compounds provided in this invention are positive allostericmodulators (PAMs) of metabotropic glutamate receptors, in particularthey are positive allosteric modulators of mGluR2. The compounds of thepresent invention do not appear to bind to the glutamate recognitionsite, the orthosteric ligand site, but instead to an allosteric sitewithin the seven transmembrane region of the receptor. In the presenceof glutamate or an agonist of mGluR2, the compounds of this inventionincrease the mGluR2 response. The compounds provided in this inventionare expected to have their effect at mGluR2 by virtue of their abilityto increase the response of such receptors to glutamate or mGluR2agonists.

As used herein, the term “treatment” is intended to refer to allprocesses, wherein there may be a slowing, interrupting, arresting orstopping of the progression of a disease or an alleviation of symptoms,but does not necessarily indicate a total elimination of all symptoms.

Hence, the present invention relates to a compound according to thegeneral Formula (I), the stereoisomeric forms and the tautomers thereofand the pharmaceutically acceptable acid or base addition salts and thesolvates thereof, for use as a medicament.

The invention also relates to the use of a compound according to thegeneral Formula (I), the stereoisomeric forms and the tautomers thereofand the pharmaceutically acceptable acid or base addition salts and thesolvates thereof, or a pharmaceutical composition according to theinvention for the manufacture of a medicament.

The invention also relates to a compound according to the generalFormula (I), the stereoisomeric forms and the tautomers thereof and thepharmaceutically acceptable acid or base addition salts and the solvatesthereof, or a pharmaceutical composition according to the invention foruse in the treatment or prevention of, in particular treatment of, acondition in a mammal, including a human, the treatment or prevention ofwhich is affected or facilitated by the neuromodulatory effect ofallosteric modulators of mGluR2, in particular positive allostericmodulators thereof.

The present invention also relates to the use of a compound according tothe general Formula (I), the stereoisomeric forms and the tautomersthereof and the pharmaceutically acceptable acid or base addition saltsand the solvates thereof, or a pharmaceutical composition according tothe invention for the manufacture of a medicament for the treatment orprevention of, in particular treatment of, a condition in a mammal,including a human, the treatment or prevention of which is affected orfacilitated by the neuromodulatory effect of allosteric modulators ofmGluR2, in particular positive allosteric modulators thereof.

The present invention also relates to a compound according to thegeneral Formula (I), the stereoisomeric forms and the tautomers thereofand the pharmaceutically acceptable acid or base addition salts and thesolvates thereof, or a pharmaceutical composition according to theinvention for use in the treatment, prevention, amelioration, control orreduction of the risk of various neurological and psychiatric disordersassociated with glutamate dysfunction in a mammal, including a human,the treatment or prevention of which is affected or facilitated by theneuromodulatory effect of positive allosteric modulators of mGluR2.

Also, the present invention relates to the use of a compound accordingto the general Formula (I), the stereoisomeric forms and the tautomersthereof and the pharmaceutically acceptable acid or base addition saltsand the solvates thereof, or a pharmaceutical composition according tothe invention for the manufacture of a medicament for treating,preventing, ameliorating, controlling or reducing the risk of variousneurological and psychiatric disorders associated with glutamatedysfunction in a mammal, including a human, the treatment or preventionof which is affected or facilitated by the neuromodulatory effect ofpositive allosteric modulators of mGluR2.

In particular, the neurological and psychiatric disorders associatedwith glutamate dysfunction, include one or more of the followingconditions or diseases: acute neurological and psychiatric disorderssuch as, for example, cerebral deficits subsequent to cardiac bypasssurgery and grafting, stroke, cerebral ischemia, spinal cord trauma,head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronaldamage, dementia (including AIDS-induced dementia), Alzheimer's disease,Huntington's Chorea, amyotrophic lateral sclerosis, ocular damage,retinopathy, cognitive disorders, idiopathic and drug-inducedParkinson's disease, muscular spasms and disorders associated withmuscular spasticity including tremors, epilepsy, convulsions, migraine(including migraine headache), urinary incontinence, substancedependence/abuse, substance withdrawal (including substances such as,for example, opiates, nicotine, tobacco products, alcohol,benzodiazepines, cocaine, sedatives, hypnotics, etc.), psychosis,schizophrenia, anxiety (including generalized anxiety disorder, panicdisorder, and obsessive compulsive disorder), mood disorders (includingdepression, major depressive disorder, treatment resistant depression,mania, bipolar disorders, such as bipolar mania), posttraumatic stressdisorder, trigeminal neuralgia, hearing loss, tinnitus, maculardegeneration of the eye, emesis, brain edema, pain (including acute andchronic states, severe pain, intractable pain, neuropathic pain, andpost-traumatic pain), tardive dyskinesia, sleep disorders (includingnarcolepsy), attention deficit/hyperactivity disorder, and conductdisorder.

In particular, the condition or disease is a central nervous systemdisorder selected from the group of anxiety disorders, psychoticdisorders, personality disorders, substance-related disorders, eatingdisorders, mood disorders, migraine, epilepsy or convulsive disorders,childhood disorders, cognitive disorders, neurodegeneration, autisticdisorders, neurotoxicity and ischemia.

In particular, the central nervous system disorder is an anxietydisorder, selected from the group of agoraphobia, generalized anxietydisorder (GAD), mixed anxiety and depression, obsessive-compulsivedisorder (OCD), panic disorder, posttraumatic stress disorder (PTSD),social phobia and other phobias. An additional anxiety disorder is panicattack.

In particular, the central nervous system disorder is a psychoticdisorder selected from the group of schizophrenia, delusional disorder,schizoaffective disorder, schizophreniform disorder andsubstance-induced psychotic disorder; more in particular, negativesymptoms or residual symptoms of schizophrenia. Such disorders manifestpsychosis as a prominent symptom. Therefore, the invention also relatesto a compound according to the general Formula (I), the stereoisomericforms and the tautomers thereof and the pharmaceutically acceptable acidor base addition salts and the solvates thereof, or a pharmaceuticalcomposition according to the invention for use in the treatment,prevention, amelioration, control or reduction of psychosis.

In particular, the central nervous system disorder is a personalitydisorder selected from the group of obsessive-compulsive personalitydisorder, borderline personality disorder and schizoid, schizotypaldisorder.

In particular, the central nervous system disorder is a substance abuseor substance-related disorder selected from the group of alcohol abuse,alcohol addiction, alcohol dependence, alcohol withdrawal, alcoholwithdrawal delirium, alcohol-induced psychotic disorder, amphetamineaddiction, amphetamine dependence, amphetamine withdrawal, cocaineaddiction, cocaine dependence, cocaine withdrawal, nicotine addiction,nicotine dependence, nicotine withdrawal, opioid dependence and opioidwithdrawal. The treatment or prevention of the substance abuse orsubstance-related disorders referred to herein may involve relapseprevention thereof.

In particular, the central nervous system disorder is an eating disorderselected from the group of anorexia nervosa and bulimia nervosa.

In particular, the central nervous system disorder is a mood disorderselected from the group of bipolar disorders (I & II), cyclothymicdisorder, depression, dysthymic disorder, major depressive disorder,treatment resistant depression, bipolar depression, andsubstance-induced mood disorder.

In particular, the central nervous system disorder is migraine.

In particular, the central nervous system disorder is epilepsy or aconvulsive disorder selected from the group of generalized nonconvulsiveepilepsy, generalized convulsive epilepsy, petit mal status epilepticus,grand mal status epilepticus, partial epilepsy with or withoutimpairment of consciousness, infantile spasms, epilepsy partialiscontinua, and other forms of epilepsy. Additional disorders encompassedunder epilepsy or convulsive disorder include any disorder in which asubject (preferably a human adult, child or infant) experiences one ormore seizures and/or tremors. Suitable examples include, but are notlimited to, epilepsy (including, but not limited to,localization-related epilepsies, generalized epilepsies, epilepsies withboth generalized and local seizures, and the like), partial-onsetseizures with or without generalization, myoclonic seizures, primarygeneralized tonic-clonic seizures in particular in patients withidiopathic generalized epilepsy, seizures associated with Lennox-Gastautsyndrome, seizures as a complication of a disease or condition (such asseizures associated with encephalopathy, phenylketonuria, juvenileGaucher's disease, Lundborg's progressive myoclonic epilepsy, stroke,head trauma, stress, hormonal changes, drug use or withdrawal, alcoholuse or withdrawal, sleep deprivation, fever, infection, and the like),status epilepticus (convulsive or non convulsive), essential tremor,restless limb syndrome, and the like. Preferably, the disorder isselected from epilepsy (regardless of type, underlying cause or origin),essential tremor or restless limb syndrome. More preferably, thedisorder is epilepsy (regardless of type, underlying cause or origin) oressential tremor. In particular, the disorder is epilepsy (regardless oftype, underlying cause or origin). A more particular example of epilepsyis refractory epilepsy, also referred to as treatment or therapyresistant epilepsy. This term is often used when patients have failedthree or more anti-epileptic drugs (AEDs). Refractory epilepsy alsoincludes refractory partial epilepsy and refractory generalized epilepsy(including idiopathic or symptomatic).

In particular, the central nervous system disorder isattention-deficit/hyperactivity disorder.

In particular, the central nervous system disorder is an autisticdisorder selected from autism and autism spectrum disorders, such asAsperger's syndrome.

In particular, the central nervous system disorder is a cognitivedisorder selected from the group of delirium, substance-inducedpersisting delirium, dementia, dementia due to HIV disease, dementia dueto Huntington's disease, dementia due to Parkinson's disease, dementiaof the Alzheimer's type, behavioral and psychological symptoms ofdementia, substance-induced persisting dementia and mild cognitiveimpairment.

Particular examples of behavioral and psychological symptoms of dementia(BPSD) include, but are not limited to, aggression, agitation andpsychosis.

In particular, the central nervous system disorder is selected from thegroup of schizophrenia, behavioral and psychological symptoms ofdementia, major depressive disorder, treatment resistant depression,bipolar depression, anxiety, depression, generalised anxiety disorder,post-traumatic stress disorder, bipolar mania, epilepsy,attention-deficit/hyperactivity disorder, substance abuse and mixedanxiety and depression.

In particular, the central nervous system disorder is selected from thegroup of schizophrenia, epilepsy, obsessive compulsive disorder, alcoholaddiction, cocaine addiction, nicotine addiction, borderline personalitydisorder, bipolar disorder, behavioral and psychological symptoms ofdementia, Asperger's syndrome, major depressive disorder, treatmentresistant depression, anxiety, depression, generalised anxiety disorder,and mixed anxiety and depression.

In particular, the central nervous system disorder is selected from thegroup of schizophrenia (in particular, negative symptoms or residualsymptoms thereof), generalized anxiety disorder, bipolar disorder (I orII), migraine, behavioral and psychological symptoms of dementia,epilepsy or convulsive disorders, panic disorder, mixed anxiety anddepression, and agoraphobia.

In particular, the central nervous system disorder is selected from thegroup of schizophrenia (in particular, negative symptoms or residualsymptoms thereof), generalized anxiety disorder, bipolar disorder (I orII), migraine, epilepsy, panic disorder, mixed anxiety and depression,and agoraphobia. Of the disorders mentioned above, the treatment ofpsychosis, schizophrenia, behavioral and psychological symptoms ofdementia, major depressive disorder, treatment resistant depression,bipolar depression, anxiety, depression, generalised anxiety disorder,post-traumatic stress disorder, bipolar mania, substance abuse and mixedanxiety and depression, are of particular importance.

Of the disorders mentioned above, the treatment of generalized anxietydisorder, bipolar disorder (I or II), epilepsy, panic disorder, andagoraphobia are of particular importance.

Of the disorders mentioned above, the treatment of anxiety,schizophrenia, migraine, depression, and epilepsy are of particularimportance.

Of the disorders mentioned above, the treatment of anxiety and epilepsyare of particular importance.

At present, the fourth edition of the Diagnostic & Statistical Manual ofMental Disorders (DSM-IV) of the American Psychiatric Associationprovides a diagnostic tool for the identification of the disordersdescribed herein. The person skilled in the art will recognize thatalternative nomenclatures, nosologies, and classification systems forneurological and psychiatric disorders described herein exist, and thatthese evolve with medical and scientific progresses.

A skilled person will be familiar with alternative nomenclatures,nosologies, and classification systems for the diseases or conditionsreferred to herein. For example, the “American Psychiatric Association:Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition.Arlington, Va., American Psychiatric Association, 2013” (DSM-5™)utilizes terms such as anxiety disorders, in particular, agoraphobia,generalized anxiety disorder, panic disorder, social anxiety disorder(social phobia), and panic attack; schizophrenia spectrum and otherpsychotic disorders, in particular, schizophrenia, delusional disorder,schizoaffective disorder, schizophreniform disorder,substance/medication-induced and psychotic disorder; personalitydisorders, in particular, obsessive-compulsive personality disorder,borderline personality disorder, schizoid personality disorder, andschizotypal personality disorder; substance-related and addictivedisorders, in particular, alcohol use disorder, alcohol withdrawal,opioid use disorder, opioid withdrawal, stimulant (amphetamine-typesubstance, cocaine) use disorder, stimulant (amphetamine-type substance,cocaine) withdrawal, tobacco use disorder, and tobacco withdrawal;depressive disorders, in particular, major depressive disorder,persistent depressive disorder (dysthymia), andsubstance/medication-induced depressive disorder; bipolar and relateddisorders, in particular, bipolar I disorder, bipolar II disorder,cyclothymic disorder, substance/medication-induced bipolar and relateddisorder; obsessive-compulsive disorder and related disorders, inparticular, obsessive-compulsive disorder; trauma- and stressor-relateddisorders, in particular, posttraumatic stress disorder, and acutestress disorder; neurodevelopmental disorder, in particular, autismspectrum disorder, and attention-deficit/hyperactivity disorder;neurocognitive disorders (NCDs) (both major and mild), in particular,delirium, substance intoxication delirium, NCD due to Alzheimer'sdisease, NCD due to HIV infection, NCD due to Huntington's disease, NCDdue to Parkinson's disease, and substance/medication-induced NCD. Suchterms may be used by the skilled person as an alternative nomenclaturefor some of the diseases or conditions referred to herein.

Therefore, the invention also relates to a compound according to thegeneral Formula (I), the stereoisomeric forms and the tautomers thereofand the pharmaceutically acceptable acid or base addition salts and thesolvates thereof, for use in the treatment of any one of the diseasesmentioned hereinbefore.

The invention also relates to a compound according to the generalFormula (I), the stereoisomeric forms and the tautomers thereof and thepharmaceutically acceptable acid or base addition salts and the solvatesthereof, for use in treating any one of the diseases mentionedhereinbefore.

The invention also relates to a compound according to the generalFormula (I), the stereoisomeric forms and the tautomers thereof and thepharmaceutically acceptable acid or base addition salts and the solvatesthereof, for the treatment or prevention, in particular treatment, ofany one of the diseases mentioned hereinbefore.

The invention also relates to the use of a compound according to thegeneral Formula (I), the stereoisomeric forms and the tautomers thereofand the pharmaceutically acceptable acid or base addition salts and thesolvates thereof, for the manufacture of a medicament for the treatmentor prevention of any one of the disease conditions mentionedhereinbefore.

The invention also relates to the use of a compound according to thegeneral Formula (I), the stereoisomeric forms and the tautomers thereofand the pharmaceutically acceptable acid or base addition salts and thesolvates thereof, for the manufacture of a medicament for the treatmentof any one of the disease conditions mentioned hereinbefore.

The compounds of the present invention can be administered to mammals,preferably humans, for the treatment or prevention of any one of thediseases mentioned hereinbefore.

In view of the utility of the compounds of Formula (I), there isprovided a method of treating warm-blooded animals, including humans,suffering from any one of the diseases mentioned hereinbefore, and amethod of preventing in warm-blooded animals, including humans, any oneof the diseases mentioned hereinbefore.

Said methods comprise the administration, i.e. the systemic or topicaladministration, preferably oral administration, of a therapeuticallyeffective amount of a compound of Formula (I), a stereoisomeric form ora tautomer thereof and a pharmaceutically acceptable addition salt orsolvate thereof, to warm-blooded animals, including humans.

Therefore, the invention also relates to a method for the preventionand/or treatment of any one of the diseases mentioned hereinbeforecomprising administering a therapeutically effective amount of acompound according to the invention to a patient in need thereof.

One skilled in the art will recognize that a therapeutically effectiveamount of the PAMs of the present invention is the amount sufficient tomodulate the activity of the mGluR2 and that this amount varies interalia, depending on the type of disease, the concentration of thecompound in the therapeutic formulation, and the condition of thepatient. Generally, an amount of PAM to be administered as a therapeuticagent for treating diseases in which modulation of the mGluR2 isbeneficial, such as the disorders described herein, will be determinedon a case by case by an attending physician.

Generally, a suitable dose is one that results in a concentration of thePAM at the treatment site in the range of 0.5 nM to 200 μM, and moreusually 5 nM to 50 μM. To obtain these treatment concentrations, apatient in need of treatment likely will be administered an effectivetherapeutic daily amount of about 0.01 mg/kg to about 50 mg/kg bodyweight, preferably from about 0.01 mg/kg to about 25 mg/kg body weight,more preferably from about 0.01 mg/kg to about 10 mg/kg body weight,more preferably from about 0.01 mg/kg to about 2.5 mg/kg body weight,even more preferably from about 0.05 mg/kg to about 1 mg/kg body weight,more preferably from about 0.1 to about 0.5 mg/kg body weight. Theamount of a compound according to the present invention, also referredto here as the active ingredient, which is required to achieve atherapeutically effect will, of course vary on case-by-case basis, varywith the particular compound, the route of administration, the age andcondition of the recipient, and the particular disorder or disease beingtreated. A method of treatment may also include administering the activeingredient on a regimen of between one and four intakes per day. Inthese methods of treatment the compounds according to the invention arepreferably formulated prior to admission. As described herein below,suitable pharmaceutical formulations are prepared by known proceduresusing well known and readily available ingredients.

Because such positive allosteric modulators of mGluR2, includingcompounds of Formula (I), enhance the response of mGluR2 to glutamate,it is an advantage that the present methods utilize endogenousglutamate.

Because positive allosteric modulators of mGluR2, including compounds ofFormula (I), enhance the response of mGluR2 to agonists, it isunderstood that the present invention extends to the treatment ofneurological and psychiatric disorders associated with glutamatedysfunction by administering an effective amount of a positiveallosteric modulator of mGluR2, including compounds of Formula (I), incombination with an mGluR2 agonist (or mGluR2/3 agonist). Examples ofmGluR2/mGluR2/3 agonists include, for example, LY-379268; DCG-IV;LY-354740; LY-404039; LY-544344; LY-2140023; LY-181837; LY-389795;LY-446433; LY-450477; talaglumetad; MGS0028; MGS0039;(−)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate;(+)-4-amino-2-sulfonylbicyclo[3.1.0]hexane-4,6-dicarboxylic acid;(+)-2-amino-4-fluorobicyclo-[3.1.0]hexane-2,6-dicarboxylic acid;1S,2R,5S,6S-2-amino-6-fluoro-4-oxobicyclo-[3.1.0]hexane-2,6-dicarboxylicacid;1S,2R,4S,5S,6S-2-amino-6-fluoro-4-hydroxybicyclo[3.1.0]hexane-2,6-dicarboxylicacid;1S,2R,3R,5S,6S-2-amino-3-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylicacid;1S,2R,3S,5S,6S-2-amino-6-fluoro-3-hydroxybicyclo[3.1.0]hexane-2,6-dicarboxylicacid; (+)-4-amino-2-sulfonylbicyclo-[3.1.0]hexane-4,6-dicarboxylic acid;(+)-2-amino-4-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid;1S,2R,5S,6S-2-amino-6-fluoro-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylicacid;1S,2R,4S,5S,6S-2-amino-6-fluoro-4-hydroxybicyclo[3.1.0]hexane-2,6-dicarboxylicacid;1S,2R,3R,5S,6S-2-amino-3-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylicacid; or1S,2R,3S,5S,6S-2-amino-6-fluoro-3-hydroxybicyclo-[3.1.0]hexane-2,6-dicarboxylicacid. More preferable mGluR2 agonists include LY-379268; DCG-IV;LY-354740; LY-404039; LY-544344; or LY-2140023.

The compounds of the present invention may be utilized in combinationwith one or more other drugs in the treatment, prevention, control,amelioration, or reduction of risk of diseases or conditions for whichcompounds of Formula (I) or the other drugs may have utility, where thecombination of the drugs together are safer or more effective thaneither drug alone.

Pharmaceutical Compositions

The present invention also provides compositions for preventing ortreating diseases in which modulation of the mGlu2 receptor isbeneficial, such as the disorders described herein. While it is possiblefor the active ingredient to be administered alone, it is preferable topresent it as a pharmaceutical composition. Accordingly, the presentinvention also relates to a pharmaceutical composition comprising apharmaceutically acceptable carrier or diluent and, as activeingredient, a therapeutically effective amount of a compound accordingto the invention, in particular a compound according to Formula (I), apharmaceutically acceptable salt thereof, a solvate thereof or astereochemically isomeric form or a tautomer thereof. The carrier ordiluent must be “acceptable” in the sense of being compatible with theother ingredients of the composition and not deleterious to therecipients thereof.

The compounds according to the invention, in particular the compoundsaccording to Formula (I), the pharmaceutically acceptable salts thereof,the solvates and the stereochemically isomeric forms and the tautomersthereof, or any subgroup or combination thereof may be formulated intovarious pharmaceutical forms for administration purposes. As appropriatecompositions there may be cited all compositions usually employed forsystemically administering drugs.

The pharmaceutical compositions of this invention may be prepared by anymethods well known in the art of pharmacy, for example, using methodssuch as those described in Gennaro et al. Remington's PharmaceuticalSciences (18^(th) ed., Mack Publishing Company, 1990, see especiallyPart 8: Pharmaceutical preparations and their Manufacture). To preparethe pharmaceutical compositions of this invention, a therapeuticallyeffective amount of the particular compound, optionally in salt form, asthe active ingredient is combined in intimate admixture with apharmaceutically acceptable carrier or diluent, which carrier or diluentmay take a wide variety of forms depending on the form of preparationdesired for administration. These pharmaceutical compositions aredesirable in unitary dosage form suitable, in particular, for oral,topical, rectal or percutaneous administration, by parenteral injectionor by inhalation. For example, in preparing the compositions in oraldosage form, any of the usual pharmaceutical media may be employed suchas, for example, water, glycols, oils, alcohols and the like in the caseof oral liquid preparations such as, for example, suspensions, syrups,elixirs, emulsions and solutions; or solid carriers such as, forexample, starches, sugars, kaolin, diluents, lubricants, binders,disintegrating agents and the like in the case of powders, pills,capsules and tablets. Because of the ease in administration, oraladministration is preferred, and tablets and capsules represent the mostadvantageous oral dosage unit forms in which case solid pharmaceuticalcarriers are obviously employed. For parenteral compositions, thecarrier will usually comprise sterile water, at least in large part,though other ingredients, for example, surfactants, to aid solubility,may be included. Injectable solutions, for example, may be prepared inwhich the carrier comprises saline solution, glucose solution or amixture of saline and glucose solution. Injectable suspensions may alsobe prepared in which case appropriate liquid carriers, suspending agentsand the like may be employed. Also included are solid form preparationsthat are intended to be converted, shortly before use, to liquid formpreparations. In the compositions suitable for percutaneousadministration, the carrier optionally comprises a penetration enhancingagent and/or a suitable wetting agent, optionally combined with suitableadditives of any nature in minor proportions, which additives do notintroduce a significant deleterious effect on the skin. Said additivesmay facilitate the administration to the skin and/or may be helpful forpreparing the desired compositions. These compositions may beadministered in various ways, e.g., as a transdermal patch, as aspot-on, as an ointment.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in unit dosage form for ease ofadministration and uniformity of dosage. Unit dosage form as used hereinrefers to physically discrete units suitable as unitary dosages, eachunit containing a predetermined quantity of active ingredient calculatedto produce the desired therapeutic effect in association with therequired pharmaceutical carrier. Examples of such unit dosage forms aretablets (including scored or coated tablets), capsules, pills, powderpackets, wafers, suppositories, injectable solutions or suspensions andthe like, teaspoonfuls, tablespoonfuls, and segregated multiplesthereof.

Since the compounds according to the invention are orally administrablecompounds, pharmaceutical compositions comprising aid compounds for oraladministration are especially advantageous.

In order to enhance the solubility and/or the stability of the compoundsof Formula (I) in pharmaceutical compositions, it can be advantageous toemploy α-, β- or γ-cyclodextrins or their derivatives, in particularhydroxyalkyl substituted cyclodextrins, e.g.2-hydroxypropyl-β-cyclodextrin or sulfobutyl-β-cyclodextrin. Alsoco-solvents such as alcohols may improve the solubility and/or thestability of the compounds according to the invention in pharmaceuticalcompositions.

The exact dosage and frequency of administration depends on theparticular compound of formula (I) used, the particular condition beingtreated, the severity of the condition being treated, the age, weight,sex, extent of disorder and general physical condition of the particularpatient as well as other medication the individual may be taking, as iswell known to those skilled in the art. Furthermore, it is evident thatsaid effective daily amount may be lowered or increased depending on theresponse of the treated subject and/or depending on the evaluation ofthe physician prescribing the compounds of the instant invention.

Depending on the mode of administration, the pharmaceutical compositionwill comprise from 0.05 to 99% by weight, preferably from 0.1 to 70% byweight, more preferably from 0.1 to 50% by weight of the activeingredient, and, from 1 to 99.95% by weight, preferably from 30 to 99.9%by weight, more preferably from 50 to 99.9% by weight of apharmaceutically acceptable carrier, all percentages being based on thetotal weight of the composition.

The amount of a compound of Formula (I) that can be combined with acarrier material to produce a single dosage form will vary dependingupon the disease treated, the mammalian species, and the particular modeof administration. However, as a general guide, suitable unit doses forthe compounds of the present invention can, for example, preferablycontain between 0.1 mg to about 1000 mg of the active compound. Apreferred unit dose is between 1 mg to about 500 mg. A more preferredunit dose is between 1 mg to about 300 mg. Even more preferred unit doseis between 1 mg to about 100 mg. Such unit doses can be administeredmore than once a day, for example, 2, 3, 4, 5 or 6 times a day, butpreferably 1 or 2 times per day, so that the total dosage for a 70 kgadult is in the range of 0.001 to about 15 mg per kg weight of subjectper administration. A preferred dosage is 0.01 to about 1.5 mg per kgweight of subject per administration, and such therapy can extend for anumber of weeks or months, and in some cases, years. It will beunderstood, however, that the specific dose level for any particularpatient will depend on a variety of factors including the activity ofthe specific compound employed; the age, body weight, general health,sex and diet of the individual being treated; the time and route ofadministration; the rate of excretion; other drugs that have previouslybeen administered; and the severity of the particular disease undergoingtherapy, as is well understood by those of skill in the area.

A typical dosage can be one 1 mg to about 100 mg tablet or 1 mg to about300 mg taken once a day, or, multiple times per day, or one time-releasecapsule or tablet taken once a day and containing a proportionallyhigher content of active ingredient. The time-release effect can beobtained by capsule materials that dissolve at different pH values, bycapsules that release slowly by osmotic pressure, or by any other knownmeans of controlled release.

It can be necessary to use dosages outside these ranges in some cases aswill be apparent to those skilled in the art. Further, it is noted thatthe clinician or treating physician will know how and when to start,interrupt, adjust, or terminate therapy in conjunction with individualpatient response.

As already mentioned, the invention also relates to a pharmaceuticalcomposition comprising the compounds according to the invention and oneor more other drugs for use as a medicament or for use in the treatment,prevention, control, amelioration, or reduction of risk of diseases orconditions for which compounds of Formula (I) or the other drugs mayhave utility. The use of such a composition for the manufacture of amedicament as well as the use of such a composition for the manufactureof a medicament in the treatment, prevention, control, amelioration orreduction of risk of diseases or conditions for which compounds ofFormula (I) or the other drugs may have utility are also contemplated.The present invention also relates to a combination of a compoundaccording to the present invention and an mGluR2 orthosteric agonist (ora mGluR2/3 orthosteric agonist). The present invention also relates tosuch a combination for use as a medicine. The present invention alsorelates to a product comprising (a) a compound according to the presentinvention, a pharmaceutically acceptable salt thereof or a solvatethereof, and (b) a mGluR2 orthosteric agonist (or a mGluR2/3 orthostericagonist), as a combined preparation for simultaneous, separate orsequential use in the treatment or prevention of a condition in amammal, including a human, the treatment or prevention of which isaffected or facilitated by the neuromodulatory effect of mGluR2allosteric modulators, in particular positive mGluR2 allostericmodulators. The different drugs of such a combination or product may becombined in a single preparation together with pharmaceuticallyacceptable carriers or diluents, or they may each be present in aseparate preparation together with pharmaceutically acceptable carriersor diluents.

The following examples are intended to illustrate but not to limit thescope of the present invention.

Chemistry

Several methods for preparing the compounds of this invention areillustrated in the following Examples. Unless otherwise noted, allstarting materials were obtained from commercial suppliers and usedwithout further purification.

Hereinafter, “aq.” means aqueous; “DCE” means 1,2-dichloroethane, “DCM”means dichloromethane; “DIPE” means diisopropylether; “DIPEA” meansN,N-diisopropylethylamine; “DMF” means N,N-dimethylformamide; “ES” meanselectrospray; “Et₃N” means triethylamine; “Et₂O” means diethyl ether;“EtOAc” means ethyl acetate; “h” means hours; “HPLC” means highperformance liquid chromatography; “HRMS” means high-resolution massspectra/spectrometry; “l” or “L” means liter; “LRMS” meanslow-resolution mass spectrometry/spectra; “MeOH” means methanol; “min”means minute(s); “mp” means melting point; “Pd(PPh₃)₄” meanstetrakis(triphenylphosphine)palladium(0); “RP” means reverse phase;“r.t.” means room temperature; “s” means seconds; “sat.” meanssaturated; “SFC” means supercritical fluid chromatography; “sol.” meanssolution; “THF” means tetrahydrofuran.Microwave assisted reactions were performed in a single-mode reactor:Initiator™ Sixty EXP microwave reactor (Biotage AB), or in a multimodereactor: MicroSYNTH Labstation (Milestone, Inc.).

Thin layer chromatography (TLC) was carried out on silica gel 60 F254plates (Merck) using reagent grade solvents. Open column chromatographywas performed on silica gel, particle size 60 Å, mesh=230-400 (Merck)using standard techniques. Automated flash column chromatography wasperformed using ready-to-connect cartridges from Merck, on irregularsilica gel, particle size 15-40 μm (normal phase disposable flashcolumns) on a SPOT or LAFLASH system from Armen Instrument.

The absolute stereochemical configuration for some of the compounds wasdetermined using vibrational circular dichroism (VCD). They weremeasured on a Bruker Equinox 55 equipped with a PMA 37, in a KBr liquidcell using CD₂Cl₂ as solvent (PEM: 1350 cm-1, LIA: 1 mV, resolution: 4cm⁻¹). A description on the use of VCD for the determination of absoluteconfiguration can be found in Dyatkin A. B. et. al, Chirality,14:215-219 (2002).

Whenever the notation “RS” is indicated herein, it denotes that thecompound is a racemic mixture, unless otherwise indicated. Thestereochemical configuration for some compounds has been designated “R”or “S” when the mixture was separated; for some compounds, thestereochemical configuration has been designated as “*R” or “*S” whenthe absolute stereochemistry is undetermined although the compounditself has been isolated as a single stereoisomer and isenantiomerically pure. The enantiomeric excess of compounds reportedherein was determined by analysis of the racemic mixture bysupercritical fluid chromatography (SFC) followed by SFC comparison ofthe separated enantiomer(s).

Preparation of Intermediates Description 1 Intermediate 1

Cyclopropylacetic acid ([CAS 5239-82-7], 50 g, 500 mmol) was dissolvedin CH₂Cl₂ (300 mL) then SOCl₂ (100 mL) was added. The reaction mixturewas stirred at 60° C. for 2 h and then the solvent was evaporated toyield intermediate 1 (53 g, 90%), which was used without furtherpurification.

Description 2 Intermediate 2

To a solution of 2,4-dichloro-3-iodopyridine ([CAS 343781-36-2], 290 g,1058 mmol) in DMF (1.7 L) was added methyl2,2-difluoro-2-(fluorosulfonyl)acetate ([CAS 680-15-9], 403 g, 2098mmol) and CuI (403 g, 2.13 mol), the reaction was then heated at 100° C.for 5 h.The reaction was cooled and filtered. The filtrate was diluted with H₂Oand extracted with Et₂O and washed with a NH₃ solution. The organiclayer was dried (Na₂SO₄), filtered and concentrated in vacuo to yieldintermediate 2 (160 g), which was used without further purification.

Description 3 Intermediate 3

To a solution of NaH (60% in oil, 24 g, 600 mmol) in DMF (2 L) at 0° C.was added benzyl alcohol (35 g, 325 mmol), then the reaction was stirredfor 2 min. Intermediate 2 (160 mg, 741 mmol) was added in one portion,and stirred at 0° C. for 1 h. The reaction was diluted by the additionof H₂O and extracted with Et₂O. The organic layer was dried (Na₂SO₄),filtered and concentrated in vacuo. The residue was purified by columnchromatography over silica gel (eluent: petroleum ether/EtOAc=20/1). Thepure fractions were collected and the solvent was evaporated to yieldintermediate 3 (100 g, 38%).

Description 4 Intermediate 4

To a solution of intermediate 3 (100 g, 277 mmol) in 1,4-dioxane (1.5 L)was added NH₂NH₂ hydrate (85% solution in water, 300 g, 9.11 mol), thereaction was then heated in sealed tube at 160° C. for 2 h. The mixturewas concentrated in vacuo, dissolved in DCM washed with NaHCO₃. Theorganic layer was dried (Na₂SO₄), filtered and concentrated in vacuo toyield intermediate 4 (90 g, 90%), which was used without furtherpurification.

Description 5 Intermediate 5

To a solution of intermediate 4 (90 g, 318 mmol) in CH₂Cl₂ (1.5 L) wasadded triethylamine (64.3 g, 636 mmol), the mixture was cooled to 0° C.,then a solution of intermediate 1 (53 g, 449 mmol) in CH₂Cl₂ was added.The solution was stirred at RT for 1 h. The reaction mixture was washedwith a sat. aq. sol. of NaHCO₃, and extracted with CH₂Cl₂. The organiclayer was dried (Na₂SO₄), filtered and concentrated in vacuo to yieldintermediate 5 (104.4 g, 90%).The following intermediates were synthesized following a syntheticsequence analogous to that reported in Description 5 (D5).

Intermediate Acid chloride Conditions

propionyl chloride ([CAS 79-03-8]) Addition run at RT.

cyclobutaneacetyl chloride ([CAS 59543-38-3] Conditions as in D5.

2-ethoxy-acetyl chloride ([CAS 14077-58-8]) Conditions as in D5.

butyryl chloride ([CAS 141-75-3]) Conditions as in D5.

Description 6 (a) Intermediate 9

To a solution of intermediate 5 (101 g, 277 mmol) in CH₃CN (1.2 L) wereadded phosphorus(V) oxychloride (84.7 g, 553 mmol) andN,N-diisopropylethylamine (71.3 g, 553 mmol). The reaction mixture wasstirred at 90° C. for 38 h. The reaction was then diluted with DCM andwashed with a Na₂CO₃ solution. The organic layer was dried (Na₂SO₄),filtered and concentrated in vacuo. The residue was purified by columnchromatography over silica gel (eluent: petroleum ether/EtOAc=4/1). Thepure fractions were collected and the solvent was evaporated to yieldintermediate 9 (31.39 g, 41%).

(b) Intermediate 10

The reaction was performed in 4 batches then combined for work up andpurification. To a solution of intermediate 6 (7 g, 20.6 mmol) in DCE(50 mL), was added N,N-diisopropylethylamine (3.96 mL, 22.69 mmol) andthen phosphorus oxychloride (2.12 mL, 22.69 mmol) and the reactionmixture was heated in a microwave at 150° C. for 5 min. Then DCM wasadded and the organic layer was washed with a sat. sol. of NaHCO₃, dried(Na₂SO₄) and concentrated in vacuo to afford the desired compound, whichwas purified by column chromatography (gradient elution: DCM 100% toMeOH.NH₃ 2% in DCM) to yield intermediate 10 (2.5 g, 49%).The following intermediates were synthesized following a syntheticsequence analogous to that reported in Description 6(a) or (b).

Intermediate Starting material Conditions

Intermediate 7 Reaction performed as in (a) but in CH₃CN. After thereaction was complete, the reaction mixture was poured into ice/waterthen washed with NaHCO₃ sat. sol. And extracted with DCM, dried(Na₂SO₄), filtered and concentrated. Purification was performed in Spot(Si cartridge, eluent DCM/EtOAc up to 10-20%).

Intermediate 8 Reaction performed as in (b). Purification by flashcolumn chromatography (silica; EtOAc in DCM 0/100 to 40/60).

Intermediate 25 Reaction performed as in (a). Purification by flashcolumn chromatography (silica; MeOH in CH₂Cl₂, from 0/100 to 4/96).

Description 7 Intermediate 13

(Ph₃P)₄Pd (2.096 g, 1.81 mmol) was added to a stirred solution ofintermediate 9 (10 g, 36.28 mmol) and4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxoborolane ([CAS 75927-49-0], 7.77mL, 43.53 mmol) in deoxygenated dioxane (30 mL) and a deoxygenatedNaHCO₃ saturated solution (30 mL) under nitrogen. The mixture wasstirred at 100° C. for 18 h. The mixture was diluted with EtOAc/waterand filtered through a pad of diatomaceous earth. The filtrate wastreated with brine and extracted with EtOAc. The organic layer wasseparated, dried (Na₂SO₄), filtered and the solvents evaporated invacuo. The crude product was purified by flash column chromatography(silica; EtOAc in CH₂Cl₂ 0/100 to 5/95). The desired fractions werecollected and concentrated in vacuo to yield intermediate 13 (6.08, 63%)as a yellow solid.The following intermediates were synthesized following a syntheticsequence analogous to that reported in Description 7.

Starting Intermediate material Conditions

Inter- mediate 10 Reaction performed at 150° C. Purification by flashcolumn chromatography (silica; 7N of ammonia in methanol in DCM 0/100 to1/9).

Inter- mediate 11 Extraction with DCM, purification by flash columnchromatography (silica; MeOH in DCM 4/96).

Inter- mediate 12 Purification by flash column chromatography (silica;EtOAc in DCM 0/100 to 10/90).

Inter- mediate 26 Reaction mixture performed at 150° C. in microwave.Purification by flash column chromatography (silica; EtOAc in DCM 0/100to 10/90).

Description 8 (a) Intermediate 17

Osmium tetraoxide (2.5% in t-BuOH, 10.103 mL, 0.781 mmol) and then,sodium periodate 12.53 g, 58.58 mmol) in water (48.5 mL) were added to asuspension of Intermediate 13 (6.08 g, 20.02 mmol) in dioxane (192 mL).The mixture was stirred at room temperature for 2 h.The mixture was treated with water and EtOAc and it was filtered offthrough a pad of diatomaceous earth. The filtrate was extracted withEtOAc. The organic layer was separated, dried (Na₂SO₄), filtered and thesolvents evaporated in vacuo. The crude product was washed with Et₂O andit was filtered and dried to yield intermediate 17 (4.25 g, 79%) as abrown solid.

(b) Intermediate 18

A suspension of sodium periodate (5.04 g, 23.54 mmol) in distilled water(19 mL) was added to a stirred solution of osmium tetraoxide (2.5% int-BuOH, 4.06 mL, 0.31 mmol) and intermediate 14 (2.08 g, 7.85 mmol) indioxane (75 mL). The mixture was stirred at room temperature for 150min, and then the mixture was treated with sat NaHCO₃ and brine, andextracted with DCM. The organic layer was separated, dried (Na₂SO₄),filtered and concentrated in vacuo. The product was triturated with Et₂Oand filtered in vacuo, and finally put in desiccator at 50° C. for 18 h,to yield intermediate 18 (1.6 g, 80%) as a brown solid.The following intermediates were synthesized following a syntheticsequence analogous to that reported in Description 8.

Intermediate Starting material Conditions

Intermediate 15 Procedure as in (a).

Intermediate 16 Procedure as in (a).

Intermediate 27 Procedure as in (a), order of addition: osmium tetroxidewas added to a stirred solution of intermediate 27 in 1,4-dioxane, thena suspension of sodium periodate in water was added and the reactionmixture was stirred for 2 h at RT. No filtration through a pad ofdiatomaceous earth.

Description 9 (a) Intermediates 21a, 21b and 21c

Methylmagnesium bromide (1.4 M in THF, 12.40 mL, 17.37 mmol) was addeddropwise to a stirred suspension of intermediate 17 (4.25 g, 15.79 mmol)in THF (281.07 mL) at −20° C. under N₂ atmosphere. The mixture wasstirred at −20° C. for 45 minutes. The crude was treated with a sat.sol. of NH₄Cl and extracted with EtOAc. The organic layer was separated,dried (Na₂SO₄), filtered and concentrated in vacuo. The residue waspurified by flash column chromatography (silica; MeOH in DCM 0/100 to4/96). The desired fractions were collected and concentrated in vacuo toyield intermediate 21a (racemic mixture) (2.96 g, 66%). Intermediate 21a(1.82 g) was purified by chiral SFC: [Stationary phase: CHIRALPAK AD-H(5 μm 250×20 mm), Mobile phase: 80% CO₂, 20% EtOH] yielding 21b(R-enantiomer) (0.453 g, 10%) as a pale grey solid and intermediate 21c(S-enantiomer) (0.439 g, 10%).

(b) Intermediate 22

Methylmagnesium bromide (1.4 M in THF, 3.97 mL, 5.56 mmol) was addeddropwise to a stirred suspension of intermediate 18 (1.23 g, 5.06 mmol)in THF (90 mL) at −20° C. under N₂ atmosphere. The mixture was stirredat −20° C. for 45 minutes. The crude was treated with a sat. sol. ofNH₄Cl and extracted with EtOAc. The organic layer was separated, dried(Na₂SO₄), filtered and concentrated in vacuo. The residue was purifiedby flash column chromatography (silica; MeOH in DCM 0/100 to 4/96). Thedesired fractions were collected and concentrated in vacuo. The residuethus obtained was triturated with Et₂O to yield intermediate 22 (620 mg,35%) as a pale yellow solid.The following intermediates were synthesized following a syntheticsequence analogous to that reported in Description 9.

Starting Intermediate material Conditions

Inter- mediate 19 Procedure (b).

Inter- mediate 20 Procedure (b).

Inter- mediate 28 Procedure (b).Intermediate 24a was further separated into Intermediate 24b andIntermediate 24c:

Preparation of the Final Compounds Example 1 (a) Synthesis of Compounds4, 6 and 5

DIAD (2.07 mL, 10.52 mmol) was added dropwise to a stirred solution ofintermediate 21a (2 g, 7.01 mmol), 2,4-difluorophenol (1.00 mL, 10.52mmol) and triphenylphosphine (2.76 g, 10.52 mmol) in THF (74.18 mL) at0° C. and under nitrogen atmosphere. The mixture was stirred at 100° C.for 10 minutes under microwave irradiation. The mixture was diluted withEtOAc and washed with a sat. sol. of NaHCO₃. The organic layer wasseparated, dried (Na₂SO₄), filtered and concentrated in vacuo. Theresidue was purified by flash column chromatography (silica; MeOH in DCM0/100 to 97/3). The desired fractions were collected and concentrated invacuo. The residue was triturated with DIPE to give compound 4 (1.46 g,52%) as a white solid, which was purified by chiral SFC [Stationaryphase: Chiralpak AD (5 μm 250*30 mm, Mobile phase: 85% CO₂, 15% iPrOH)],yielding compound 6 (0.659 g, 24%) and compound 5 (0.693 g, 25%).

(b) Alternative Synthesis of Compound 6

DIAD (31.06 μL, 0.16 mmol) was added dropwise to a stirred solution ofintermediate 21b (30 mg, 0.11 mmol), 2,4-difluorophenol (15.07 μL, 0.16mmol) and triphenylphosphine (41.38 mg, 0.16 mmol) in THF (1.11 mL) at0° C. and under nitrogen atmosphere. The mixture was stirred at 100° C.for 10 minutes under microwave irradiation. The mixture was diluted withEtOAc and washed with a sat. sol. of NaHCO₃. The organic layer wasseparated, dried (Na₂SO₄), filtered and concentrated in vacuo. Theresidue was purified by flash column chromatography (silica; MeOH in DCM0/100 to 97/3). The desired fractions were collected and concentrated invacuo. The residue was triturated with DIPE to give compound 6 (40 mg,96%) as a white solid.

(c) Synthesis of Compound 6 Hydrochloride Salt (.HCl)

DIAD (207.06 μL, 1.05 mmol) was added dropwise to a stirred solution ofintermediate 21b (200 mg, 0.70 mmol), 2,4-difluorophenol (100.45 μL,1.05 mmol) and triphenylphosphine (275.84 mg, 1.0516 mmol) in THF (4 mL)at 0° C. and under nitrogen atmosphere. The mixture was stirred at 100°C. for 15 minutes under microwave irradiation. The mixture was dilutedwith EtOAc and washed with a sat. sol. of NaHCO₃. The organic layer wasseparated, dried (Na₂SO₄), filtered and concentrated in vacuo. Theresidue was purified by RP HPLC (Stationary phase: C18 XBridge 30×100 mm5 μm, Mobile phase: Gradient from 60% 0.1% NH₄CO₃H/NH₄OH pH 9 solutionin Water, 40% CH₃CN to 43% 0.1% NH₄CO₃H/NH₄OH pH 9 solution in Water,57% CH₃CN), yielding a white solid residue that was dissolved in Et₂O (8mL) and 1,4-dioxane (0.5 mL). To the solution thus obtained HCl (4M indioxane, 200 μL) was added dropwise. The white solid precipitate wasfiltered, washed with Et₂O, dried (Na₂SO₄) and evaporated under vacuum.The white residue thus obtained was triturated with Et₂O to givecompound 6.HCl (110 mg, 36%) as a white solid.The following compounds were synthesized following a synthetic sequenceanalogous to that reported in Example 1(b), starting from intermediate21b.

Co. No.

 9

10

11

12

13

14

Example 2 Synthesis of Compound 7

Procedure (a): DIAD (31.06 μL, 0.158 mmol) was added dropwise to astirred solution of intermediate 21b (30 mg, 0.105 mmol),3,5-difluorophenol (20.52 mg, 0.158 mmol) and triphenylphosphine (41.38mg, 0.158 mmol) in THF (1.113 mL) at 0° C. and under nitrogenatmosphere. The mixture was stirred at 100° C. for 10 minutes undermicrowave irradiation. The mixture was diluted with EtOAc and washedwith a sat. sol. of NaHCO₃. The organic layer was separated, dried(Na₂SO₄), filtered and concentrated in vacuo. The residue was purifiedby flash column chromatography (silica; MeOH in DCM 0/100 to 96/4). Thedesired fractions were collected and concentrated in vacuo. The residuewas triturated with DIPE to give compound 7 (21 mg, 50%) as a whitesolid.Procedure (b): Alternatively, compound 7 was also synthesized followinga synthetic sequence analogous to that reported in Example 1(b),starting from intermediate 21b.

Example 3 Synthesis of Compound 8

Procedure (a): DIAD (31.06 μL, 0.158 mmol) was added dropwise to astirred solution of intermediate 21b (30 mg, 0.105 mmol),3,4-difluorophenol (20.52 mg, 0.158 mmol) and triphenylphosphine (41.38mg, 0.158 mmol) in THF (1.11 mL) at 0° C. and under nitrogen atmosphere.The mixture was stirred at 100° C. for 10 minutes under microwaveirradiation. The mixture was diluted with EtOAc and washed with a sat.sol. of NaHCO₃. The organic layer was separated, dried (Na₂SO₄),filtered and concentrated in vacuo. The residue was purified by flashcolumn chromatography (silica; MeOH in DCM 0/100 to 96/4). The desiredfractions were collected and concentrated in vacuo. The residue wastriturated with DIPE to give compound 8 (10.6 mg, 25%) as a white solid.Procedure (b): Alternatively, compound 8 was also synthesized followinga synthetic sequence analogous to that reported in Example 1(b),starting from intermediate 21b.

Example 4 Synthesis of Compound 15

Procedure (a): DIAD (155.3 μL, 0.789 mmol) was added dropwise to astirred solution of intermediate 21b (150 mg, 0.526 mmol),2,4,6-trifluorophenol (116.8 mg, 0.789 mol) and triphenylphosphine(206.88 mg, 0.789 mmol) in THF (5.56 mL) at 0° C. and under nitrogenatmosphere. The mixture was stirred at 100° C. for 10 minutes undermicrowave. The mixture was diluted with DCM and washed with a sat. sol.of NaHCO₃. The organic layer was separated, dried (Na₂SO₄), filtered andconcentrated in vacuo. The residue was purified by flash columnchromatography (silica; MeOH/NH₃ 7 N in DCM 0/100 to 90/10). The desiredfractions were collected and concentrated in vacuo, then purified by RPHPLC (Stationary phase: C18 XBridge 30×100 mm 5 μm, Mobile phase:Gradient from 54% 0.1% NH₄CO₃H/NH₄OH pH 9 solution in Water, 46% CH₃CNto 64% 0.1% NH₄CO₃H/NH₄OH pH 9 solution in Water, 36% CH₃CN) yielding acolourless oil that was crystallized upon standing (2 days). The solidwas triturated with heptane to give compound 15 (129.8 mg, 59%) as awhite solid.Procedure (b): Alternatively, compound 15 was also synthesized followinga synthetic sequence analogous to that reported in Example 1(b),starting from intermediate 21b.

Example 5 Synthesis of Compounds 1, 2 and 3

Compounds 1, 2 and 3 were synthesized following the procedure describedin Example 1(a). Thus, reaction of DIAD (500.05 μL, 2.54 mmol),intermediate 21a (483 mg, 1.69 mmol), 4-fluorophenol (227.77 mg, 2.03mmol) and triphenylphosphine (666.14 mg, 2.54 mmol) in THF (17.91 mL) asdescribed in Example 1(a) yielded a residue that was purified by flashcolumn chromatography (silica; EtOAc in DCM 0/100 to 90/10). The desiredfractions were collected and concentrated in vacuo. The resultingresidue was triturated with DIPE to yield compound 1 (320 mg, 50%) as awhite solid, which was purified by chiral SFC [Stationary phase:Chiralpak AD (5 μm 250*30 mm, Mobile phase: 77% CO₂, 23% MeOH)],yielding compound 2 (131 mg, 20%) and compound 3 (129 mg, 20%) as whitesolids.

Example 6 Synthesis of Compounds 24, 26, and 27

Compounds 24, 26 and 27 were synthesized following the proceduredescribed in Example 1(a). Thus, reaction of DIAD (364.57 μL, 1.85mmol), intermediate 22 (320 mg, 1.23 mmol), 2,4-difluorophenol (176.86μL, 1.85 mmol) and triphenylphosphine (485.67 mg, 1.85 mmol) in THF(13.06 mL) as described in Example 1(a) yielded a residue that waspurified by flash column chromatography (silica; MeOH in DCM 0/100 to96/4). The desired fractions were collected and concentrated in vacuo toyield a colourless oil that crystallized with DIPE to give compound 24as a white solid, which was purified by RP HPLC (Stationary phase: C18XBridge 30×100 mm 5 μm; mobile phase: Gradient from 54% 0.1%NH₄CO₃H/NH₄OH pH 9 solution in Water, 46% CH₃CN to 64% 0.1%NH₄CO₃H/NH₄OH pH 9 solution in Water, 36% CH₃CN) yielding a colourlessoil that was crystallized upon trituration with heptane to give 240 mg(52%) of compound 24 as a white solid, which was then purified by chiralSFC (Stationary phase: CHIRALPAK AD-H 5 μm 250×20 mm; mobile phase: 85%CO₂, 15% iPOH (0.3% iPrNH₂)), yielding compound 26 (103 mg, 22%) andcompound 27 (107 mg, 23%).The following compounds were obtained following a synthetic sequencesimilar to that reported in Example 1(a).

The following compounds were synthesized following a synthetic sequenceanalogous to that reported in Example 1(b), starting from the indicatedintermediates.

Table 1 below lists additional compounds of Formula (I) which wereprepared by analogy to the above examples (Exp. no.).

TABLE 1 Example compounds according to Formula (I).

Co. Exp Stereo- no. no. R¹ Ar chem.  1 E5^(#)

RS  2 E5^(#)

*R  3 E5^(#)

*S  4 E1^(#)

RS  5 E1^(#)

R  6   6•HCl E1(a) and (b)^(#) E1(c)*

S  7 E2^(#)

S  8 E3^(#)

S  9 E1(b)

S 10 E1(b)

S 11 E1(b)

S 12 E1(b)

S 13 E1(b)

S 14 E1(b)

S 15 E4^(#)

S 16 E1(a)

RS 17 E1(a)

*R 18 E1(a)

*S 19 E1(b)

RS 20 E1(b)

*R 21 E1(b)

*S 22 E1(b)

*R 23 E1(b)

*S 24 E6^(#)

RS 25 E1(a)

RS 26 E6^(#)

*R 27 E6^(#)

*S 28 E1(a)

*R 29 E1(a)

*S 30 E1(b)

RS 31 E1(b)

*R 32 E1(b)

*S ^(#)indicates that the experimental procedure is described in theexamples.

Analytical Part Optical Rotations

Optical rotations were measured on a Perkin-Elmer 341 polarimeter with asodium lamp and reported as follows: [α]° (λ, c g/100 ml, solvent, T°C.).[α]_(λ) ^(T)=(100α)/(l×c): where l is the path length in dm and c is theconcentration in g/100 ml for a sample at a temperature T (° C.) and awavelength λ (in nm). If the wavelength of light used is 589 nm (thesodium D line), then the symbol D might be used instead. The sign of therotation (+ or −) should always be given. When using this equation theconcentration and solvent are always provided in parentheses after therotation. The rotation is reported using degrees and no units ofconcentration are given (it is assumed to be g/100 ml).

LCMS

For (LC)MS-characterization of the compounds of the present invention,the following methods were used.

General Procedure

The High Performance Liquid Chromatography (HPLC) measurement wasperformed using a LC pump, a diode-array (DAD) or a UV detector and acolumn as specified in the respective methods. If necessary, additionaldetectors were included (see table of methods below).Flow from the column was brought to the Mass Spectrometer (MS) which wasconfigured with an atmospheric pressure ion source. It is within theknowledge of the skilled person to set the tune parameters (e.g.scanning range, dwell time . . . ) in order to obtain ions allowing theidentification of the compound's nominal monoisotopic molecular weight(MW). Data acquisition was performed with appropriate software.Compounds are described by their experimental retention times (R_(t))and ions. If not specified differently in the table of data, thereported molecular ion corresponds to the [M+H]⁺ (protonated molecule)and/or [M−H]⁻ (deprotonated molecule). In case the compound was notdirectly ionizable the type of adduct is specified (i.e. [M+NH₄]⁺,[M+HCOO]⁻, etc. . . . ). For molecules with multiple isotopic patterns(Br, Cl . . . ), the reported value is the one obtained for the lowestisotope mass. All results were obtained with experimental uncertaintiesthat are commonly associated with the method used. Hereinafter, “SQD”means Single Quadrupole Detector, “RT” room temperature, “BEH” bridgedethylsiloxane/silica hybrid, “HSS” High Strength Silica, “DAD” DiodeArray Detector.

TABLE 2 LCMS Method codes (Flow expressed in mL/min; column temperature(T) in ° C.; Run time in minutes). Flow LCMS Instrument Column Mobilephase Gradient Col T Run time Method Waters: Agilent: A: 95% From 95% 15 1 Acquity ® Eclipse Plus CH₃COONH₄ A to 5% A 50 UPLC ®- C18 RRHD 6.5mM + 5% in 4.6 min, DAD and (1.8 μm, CH₃CN, B: held for SQD 2.1 × 50 mm)CH₃CN 0.4 min Waters: Waters: A: 95% From 95% 1 5 2 Acquity ® CSH ™ C18CH₃COONH₄ A to 5% A 50 UPLC ®- (1.7 μm, 6.5 mM + 5% in 4.6 min, DAD and2.1 × 50 mm) CH₃CN, B: held for SQD CH₃CN 0.4 min Waters: Waters: BEH A:95% 84.2% A for 0.343 6.2 3 Acquity C18 (1.7 μm, CH₃COONH₄ 0.49 min, to40 UPLC ®- 2.1 × 100 mm) 7 mM/5% 10.5% A in DAD and CH₃CN, 2.18 min,Quattro B: CH₃CN held for Micro ™ 1.94 min, back to 84.2% A in 0.73 min,held for 0.73 min. Waters: Waters: A: 95% From 95% 1 9 4 Acquity ® CSH ™C18 CH₃COONH₄ A to 5% A 50 UPLC ®- (1.7 μm, 6.5 mM + 5% in 7.8 min, DADand 2.1 × 50 mm) CH₃CN, B: held for SQD CH₃CN 1.2 min

Melting Points

Values are peak values, and are obtained with experimental uncertaintiesthat are commonly associated with this analytical method.

Mettler FP 81HT/FP90 Apparatus

For a number of compounds, melting points were determined in opencapillary tubes on a FP 81HT/FP90 apparatus (Mettler-Toledo). Meltingpoints were measured with a temperature gradient of 1, 3, 5 or 10°C./minute. Maximum temperature was 300° C. The melting point was readfrom a digital display.

TABLE 3 Physico-chemical data for some compounds, retention time (R_(t))in min, [M + H]⁺ peak (protonated molecule), LCMS method and mp (meltingpoint in ° C.). Co. Mp R_(t) LCMS Optical no. (° C.) (min) [MH⁺] methodRotation 1 156.3 2.32 380 1 2 176.9 2.93 380 3 −58.5° (589 nm, c 0.53w/v %, DMF, 20° C.) 3 177.3 2.93 380 3 +59.4° (589 nm, c 0.52 w/v %,DMF, 20° C.) 4 121.7 2.41 398 1 5 142   2.99 398.3 3 +95.7° (589 nm, c0.69 w/v %, DMF, 20° C.) 6 142.4 2.99 398.2 3 −95.4° (589 nm, c 0.7 w/v%, DMF, 20° C.) 7  170.08 2.37 398 2 −55.7° (589 nm, c 0.96 w/v %, DMF,20° C.) 8 n.d. 2.32 398 2 n.d. 9 n.d. 2.32 398 2 n.d. 10 n.d. 2.25 398 2n.d. 11 n.d. 2.28 398 2 n.d. 12 n.d. 2.16 410 2 n.d. 13 144.1 2.68 410 2n.d. 14 161.7 2.51 394 2 n.d. 15  80.3 2.37 416 2 −167.0° (589 nm, c0.55 w/v %, DMF, 20° C.) 16 n.d. 2.50 412 2 n.d. 17 n.d. 3.12 412 3 n.d.18 n.d. 3.12 412 3 n.d. 19 n.d. 2.39 402 2 n.d. 20 n.d. 2.3 402 2 n.d.21 n.d. 3.36 402 n.d. 22 n.d. 2.35 420 2 n.d. 23 n.d. 2.35 420 2 n.d. 24135.7 2.05 372 2 n.d. 25 138.3 2.13 390 2 n.d. 26 n.d. 2.80 372 3 −83.9°(589 nm, c 0.52 w/v %, DMF, 25° C.) 27 n.d. 2.80 372 3 +92.1° (589 nm, c0.55 w/v %, DMF, 25° C.) 28 n.d. 2.85 390 3 −129.2° (589 nm, c 0.5 w/v%, DMF, 25° C.) 29 n.d. 2.85 390 3 +137.3° (589 nm, c 0.51 w/v %, DMF,25° C.) 30 130.6 2.29 386 2 n.d. 31  127.85 2.29 386 2 −67.5° (589 nm, c0.83 w/v %, DMF, 20° C.) 32  127.69 2.29 386 2 +89.5° (589 nm, c 0.83w/v %, DMF, 20° C.) (n.d. = not determined).

SFC-MS General Procedure

The SFC measurement was performed using Analytical system from Bergerinstrument comprising a FCM-1200 dual pump fluid control module fordelivering carbon dioxide (CO₂) and modifier, a CTC Analytics automaticliquid sampler, a TCM-20000 thermal control module for column heatingfrom room temperature to 80° C. An Agilent 1100 UV photodiode arraydetector equipped with a high-pressure flow cell standing up to 400 barswas used. Flow from the column was split to a MS spectrometer. The MSdetector was configured with an atmospheric pressure ionization source.The following ionization parameters for the Waters ZQ massspectrophotometer are: corona: 9 μa, source temp: 140° C., cone: 30 V,probe temp 450° C., extractor 3 V, desolvatation gas 400 L/hr, cone gas70 L/hr. Nitrogen was used as the nebulizer gas. Data acquisition wasperformed with a Waters-Micromass MassLynx-Openlynx data system.Method 1: In addition to the general procedure: The analytical chiralseparation in SFC-MS was carried out on a CHIRALPAK AD DAICEL column (10μm, 4.6×250 mm) at 35° C. with a flow rate of 3.0 ml/min. The mobilephase is 85% CO₂, 15% iPrOH (+0.3% iPrNH₂) hold 7 min in isocratic mode.Method 2: In addition to the general procedure: The analytical chiralseparation in SFC-MS was carried out on a CHIRALPAK AD DAICEL column (10μm, 4.6×250 mm) at 35° C. with a flow rate of 3.0 ml/min. The mobilephase is 75% CO2, 15% iPrOH (+0.3% iPrNH₂) hold 7 min in isocratic mode.Method 3: In addition to the general procedure: The analytical chiralseparation in SFC-MS was carried out on a CHIRALPAK AD DAICEL column (10μm, 4.6×250 mm) at 35° C. with a flow rate of 3.0 ml/min. The mobilephase is 80% CO2, 10% Methanol+10% iPrOH (+0.3% iPrNH₂) hold 7 min inisocratic mode.

TABLE 4 Analytical SFC data - R_(t) means retention time (in minutes),[M + H]⁺ means the protonated mass of the compound, method refers to themethod used for SFC/MS analysis of enantiomerically pure compounds. Themeasurement was compared against the mixture. UV Isomer Co. Area ElutionNr. R_(t) [M + H]⁺ % Method Order* 6 4.28 398 100 1 A 5 5.98 398 100 1 B2 2.13 380 100 2 A 3 2.97 380 100 2 B 17 2.46 412 100 3 A 18 3.12 412100 3 B 31 2.93 386 100 1 A 32 3.81 386 100 1 B *A means the firstisomer that elutes. B means the second isomer that elutes.

Nuclear Magnetic Resonance (NMR)

For a number of compounds, ¹H NMR spectra were recorded either on aBruker DPX-400 or on a Bruker AV-500 spectrometer with standard pulsesequences, operating at 400 MHz and 500 MHz respectively. Chemicalshifts (δ) are reported in parts per million (ppm) downfield fromtetramethylsilane (TMS), which was used as internal standard.

Co. No. 6: ¹H NMR (400 MHz, CDCl₃) δ ppm 0.30-0.38 (m, 2H), 0.59-0.68(m, 2H), 1.14-1.22 (m, 1H), 1.72 (d, J=6.5 Hz, 3H), 3.02-3.14 (m, 2H),5.84 (q, J=6.3 Hz, 1H), 6.67-6.73 (m, 1H), 6.80-6.89 (m, 2H), 7.30 (d,J=7.4 Hz, 1H), 8.11 (d, J=7.4 Hz, 1H)

Co. No. 7: ¹H NMR (400 MHz, CDCl₃) δ ppm 0.30-0.39 (m, 2H), 0.59-0.68(m, 2H), 1.11-1.23 (m, 1H), 1.70 (d, J=6.5 Hz, 3H), 3.01-3.14 (m, 2H),5.83 (q, J=6.2 Hz, 1H), 6.35-6.45 (m, 3H), 7.13 (d, J=7.2 Hz, 1H), 8.08(d, J=7.4 Hz, 1H)

Co. No. 8: ¹H NMR (400 MHz, CDCl₃) δ ppm 0.30-0.38 (m, 2H), 0.58-0.68(m, 2H), 1.11-1.22 (m, 1H), 1.69 (d, J=6.2 Hz, 3H), 3.01-3.13 (m, 2H),5.79 (q, J=6.2 Hz, 1H), 6.53 (dtd, J=9.2, 3.1, 3.1, 1.7 Hz, 1H), 6.72(ddd, J=11.6, 6.5, 3.1 Hz, 1H), 6.95-7.04 (m, 1H), 7.15 (d, J=7.4 Hz,1H), 8.07 (d, J=7.4 Hz, 1H)

Co. No. 15: ¹H NMR (500 MHz, CDCl₃) δ ppm 0.30-0.41 (m, 2H), 0.59-0.71(m, 2H), 1.16-1.25 (m, 1H), 1.70 (d, J=6.4 Hz, 3H), 3.05-3.16 (m, 2H),5.80 (q, J=6.4 Hz, 1H), 6.62-6.70 (m, 2H), 7.45 (d, J=7.5 Hz, 1H), 8.16(d, J=7.2 Hz, 1H)

Co. No. 13: ¹H NMR (500 MHz, CDCl₃) δ ppm 0.27-0.39 (m, 2H), 0.58-0.67(m, 2H), 1.12-1.21 (m, 1H), 1.73 (d, J=6.4 Hz, 3H), 2.22 (s, 3H), 3.06(qd, J=15.4, 6.6 Hz, 2H), 5.92 (q, J=6.4 Hz, 1H), 6.71 (d, J=8.4 Hz,1H), 6.89 (dd, J=8.4, 1.4 Hz, 1H), 7.18 (d, J=1.7 Hz, 1H), 7.32 (d,J=7.2 Hz, 1H), 8.07 (d, J=7.2 Hz, 1H)

Co. No. 14: ¹H NMR (500 MHz, CDCl₃) δ ppm 0.28-0.39 (m, 2H), 0.57-0.69(m, 2H), 1.12-1.21 (m, 1H), 1.70 (d, J=6.6 Hz, 3H), 2.31 (s, 3H),3.01-3.12 (m, 2H), 5.79 (q, J=6.6 Hz, 1H), 6.55 (dd, J=9.0, 4.3 Hz, 1H),6.69 (td, J=8.5, 3.0 Hz, 1H), 6.87 (dd, J=9.0, 2.9 Hz, 1H), 7.17 (d,J=7.5 Hz, 1H), 8.06 (d, J=7.2 Hz, 1H)

Co. No. 20: ¹H NMR (500 MHz, CDCl₃) δ ppm 1.22 (t, J=7.1 Hz, 3H), 1.72(d, J=6.4 Hz, 3H), 3.58 (q, J=7.1 Hz, 2H), 5.03-5.10 (m, 2H), 5.84 (q,J=6.5 Hz, 1H), 6.67-6.74 (m, 1H), 6.81-6.88 (m, 2H), 7.34 (d, J=7.2 Hz,1H), 8.40 (d, J=7.5 Hz, 1H)

Co. No. 22: ¹H NMR (500 MHz, CDCl₃) δ ppm 1.23 (t, J=6.9 Hz, 3H), 1.70(d, J=6.4 Hz, 3H), 3.58 (q, J=7.0 Hz, 2H), 5.05-5.12 (m, 2H), 5.81 (q,J=6.6 Hz, 1H), 6.62-6.70 (m, 2H), 7.48 (d, J=7.5 Hz, 1H), 8.45 (d, J=7.2Hz, 1H)

Co. No. 31: ¹H NMR (400 MHz, CDCl₃) δ ppm 1.07 (t, J=7.40 Hz, 3H) 1.72(d, J=6.24 Hz, 3H) 1.92 (sxt, J=7.63 Hz, 2H) 2.98-3.14 (m, 2H) 5.84 (q,J=6.47 Hz, 1H) 6.65-6.74 (m, 1H) 6.78-6.89 (m, 2H) 7.29 (d, J=7.40 Hz,1H) 8.02 (d, J=7.40 Hz, 1H).

Pharmacological Examples A) In Vitro Pharmacology

The compounds provided in the present invention are positive allostericmodulators of mGluR2. These compounds appear to potentiate glutamateresponses by binding to an allosteric site other than the glutamatebinding site. The response of mGluR2 to a concentration of glutamate isincreased when compounds of Formula (I) are present. Compounds ofFormula (I) are expected to have their effect substantially at mGluR2 byvirtue of their ability to enhance the function of the receptor. Theeffects of positive allosteric modulators tested at mGluR2 using the[³⁵S]GTPγS binding assay method described below and which is suitablefor the identification of such compounds, and more particularly thecompounds according to Formula (I), are shown in Table 5.

[³⁵S]GTPγS Binding Assay

The [³⁵S]GTPγS binding assay is a functional membrane-based assay usedto study G-protein coupled receptor (GPCR) function wherebyincorporation of a non-hydrolysable form of GTP, [³⁵S]GTPγS (guanosine5′-triphosphate, labelled with gamma-emitting ³⁵S), is measured. TheG-protein a subunit catalyzes the exchange of guanosine 5′-diphosphate(GDP) by guanosine triphosphate (GTP) and on activation of the GPCR byan agonist, [³⁵S]GTPγS, becomes incorporated and cannot be cleaved tocontinue the exchange cycle (Harper (1998) Current Protocols inPharmacology 2.6.1-10, John Wiley & Sons, Inc.). The amount ofradioactive [³⁵S]GTPγS incorporation is a direct measure of the activityof the G-protein and hence the activity of the agonist can bedetermined. mGlu2 receptors are shown to be preferentially coupled toGαi-protein, a preferential coupling for this method, and hence it iswidely used to study receptor activation of mGlu2 receptors both inrecombinant cell lines and in tissues. Here we describe the use of the[³⁵S]GTPγS binding assay using membranes from cells transfected with thehuman mGlu2 receptor and adapted from Schaffhauser et al. (MolecularPharmacology, 2003, 4:798-810) for the detection of the positiveallosteric modulation (PAM) properties of the compounds of thisinvention.

Membrane Preparation

CHO-cells were cultured to pre-confluence and stimulated with 5 mMbutyrate for 24 h. Cells were then collected by scraping in PBS and cellsuspension was centrifuged (10 min at 4000 RPM in benchtop centrifuge).Supernatant was discarded and pellet gently resuspended in 50 mMTris-HCl, pH 7.4 by mixing with a vortex and pipetting up and down. Thesuspension was centrifuged at 16,000 RPM (Sorvall RC-5C plus rotorSS-34) for 10 minutes and the supernatant discarded. The pellet washomogenized in 5 mM Tris-HCl, pH 7.4 using an ultra-turrax homogenizerand centrifuged again (18,000 RPM, 20 min, 4° C.). The final pellet wasresuspended in 50 mM Tris-HCl, pH 7.4 and stored at −80° C. inappropriate aliquots before use. Protein concentration was determined bythe Bradford method (Bio-Rad, USA) with bovine serum albumin asstandard.

[³⁵S]GTPγS Binding Assay

Measurement of mGluR2 positive allosteric modulatory activity of testcompounds was performed as follows. Test compounds and glutamate werediluted in assay buffer containing 10 mM HEPES acid, 10 mM HEPES salt,pH 7.4, 100 mM NaCl, 3 mM MgCl₂ and 10 μM GDP. Human mGlu2receptor-containing membranes were thawed on ice and diluted in assaybuffer supplemented with 14 μg/ml saponin. Membranes were pre-incubatedwith compound alone or together with a predefined (˜EC₂₀) concentrationof glutamate (PAM assay) for 30 min at 30° C. After addition of[³⁵S]GTPγS (f c. 0.1 nM), assay mixtures were shaken briefly and furtherincubated to allow [³⁵S]GTPγS incorporation on activation (30 minutes,30° C.). Final assay mixtures contained 7 μg of membrane protein in 10mM HEPES acid, 10 mM HEPES salt, pH 7.4, 100 mM NaCl, 3 mM MgCl₂, 10 μMGDP and 2 μg/ml saponin. Total reaction volume was 2004 Reactions wereterminated by rapid filtration through Unifilter-96 GF/B plates (PerkinElmer, Massachusetts, USA) using a 96-well filtermate universalharvester. Filters were washed 6 times with ice-cold 10 mM NaH₂PO₄/10 mMNa₂HPO₄, pH 7.4. Filters were then air-dried, and 40 μl of liquidscintillation cocktail (Microscint-O) was added to each well.Membrane-bound radioactivity was counted in a Microplate Scintillationand Luminescence Counter from Perkin Elmer.

Data Analysis

The concentration-response curves of representative compounds of thepresent invention—obtained in the presence of EC₂₀ of mGluR2 agonistglutamate to determine positive allosteric modulation (PAM)—weregenerated using the Lexis software interface (developed at J&J). Datawere calculated as % of the control glutamate response, defined as themaximal response that is generated upon addition of glutamate alone.Sigmoid concentration-response curves plotting these percentages versusthe log concentration of the test compound were analyzed usingnon-linear regression analysis. The concentration producing half-maximaleffect is then calculated as EC₅₀.

The pEC₅₀ values below were calculated as the −log EC₅₀, when the EC₅₀is expressed in M. E_(max) is defined as relative maximal effect (i.e.maximal % effect relative to the control glutamate response).Table 5 below shows the pharmacological data obtained for compounds ofFormula (I).

TABLE 5 Pharmacological data for compounds according to the invention.GTPγS - GTPγS - Co. hmGluR2 hmGluR2 No. PAM pEC₅₀ PAM E_(max) 1 6.59 2962 6.84 228 3 5.79 187 6 7.39 256 5 6.06 141 4 7.04 329 7 7.31 292 8 7.04244 9 7.3 260 10 7.47 218 11 8.25 239 12 6.99 178 16 7.54 284 13 7.75280 14 7.53 281 15 8.16 293 19 6.71 297 25 6.9 233 24 6.42 193 17 7.73317 18 6.24 213 22 7.61 325 23 5.94 167 21 6.32 102 20 7.07 332 26 6.78214 27 n.c. 51 30 6.9 227 28 7.19 234 29 5.85 77 31 7.05 251 32 5.71 116n.c. means that the pEC₅₀ could not be calculated pEC₅₀ values were notcalculated in cases where the concentration-response curve did not reacha plateau level.

All compounds were tested in presence of mGluR2 agonist glutamate at apredetermined EC₂₀ concentration, to determine positive allostericmodulation. pEC₅₀ values were calculated from a concentration-responseexperiment of at least 8 concentrations.

B) In Vivo Pharmacology Motor Activity (Video Tracking) Apparatus andGeneral Procedure

On the day of experiments, the mice were brought into the proceduralroom. They were housed individually and allowed to acclimate for atleast a half hour prior to testing. Although the studies were conductedduring the light cycle (from 8:00 to 16:00 h), the procedure room wasonly sparsely lit (3 to 30 LUX) to provide better contrast for the videotracking. Local lighting was used for the injection procedures. Duringeach trial, an individual mouse was placed in an open field arena (greyPVC cylinder with a height of 40 cm and a diameter of 22.5 cm). Eacharena was placed on an infrared LED (8×8 LEDs)-lit box (white PVCsquared box; 40×40 cm²; height 12.5 cm). Each mouse was placed in thecenter of the arena and allowed to explore freely for 30 min. After eachtrial, the arena was cleaned with a wet and subsequently with a drycleaning cloth. An infrared sensitive tube camera and a white lightsource (in arena: 4-7 LUX) were mounted to the ceiling above theobservation chamber to record and input activity to a computer. Animalbehavior was recorded and analyzed using the Noldus Ethovision XT VideoTracking System (Version 3.1; Noldus, Wageningen, The Netherlands). Thetotal distance traveled (cm) was calculated. Data were then exported todata management systems for further analysis and reporting.

1) Phencyclidine (PCP)-Induced Hyperlocomotion in Mice

Test compound or solvent was administered at a pre-defined time beforemeasurement (standard: 30 min) to male NMRI mice that were challengedwith phencyclidine (PCP; 5 mg/kg, s.c.) 30 min before measurement.Activity was measured for a period of 30 min. Criterion for drug-inducedinhibition of hyperlocomotion: total distance<5500 counts (3.9% falsepositives in controls; n=154).

2) Conditioned Avoidance Response (CAR) Test in Rats

Apparatus

The apparatus consisted of an inner box surrounded by an outer box. Theinner box was composed of four walls of transparent, synthetic material(length×width×height: 30×30×30 cm), an open top, and a grid floor madeof 15 pairs of iron bars (2 mm diameter; 6 mm inter-bar distance). Oddand even bars were connected with a source of alternative current (1.0mA; Coulbourn Instruments Solid State Shocker/Distributor), which couldbe interrupted by a switch. The outer box was composed of the samematerial (length×width×height: 40×40×36 cm), also with an open top, witha distance of 5 cm between the inner and outer box on all sides. Todecrease the amount of environmental stimuli, three walls of the outerbox were made non-transparent. The front wall was left transparent toallow the necessary inspection of the animal during the test. The upperedge of the outer and inner box served as a target for the rats on whichto jump with fore- and hind-paws, respectively.

Avoidance Conditioning and Selection of Animals

From their arrival in the laboratory on the experimental day, male WigaWistar rats (230±30 g) were housed in individual cages provided withbedding material. The rats received 5 training sessions at 15-min timeintervals over a 1-h period during which, the rats were conditioned toavoid an electric shock: the rat was placed on the non-electrified gridfloor and the grid was electrified 10 s later for not more than 30 s, ifthe rat did not jump out of the box. Only rats that showed correctavoidance responses in all the last 3 training sessions were includedfor further experiments, and received the test compound or solventimmediately after the last training session.

Experimental Sessions

The rats were tested 3 times, i.e. at 60, 90 and 120 min after theinjection of test compound or solvent. Latency to avoidance wasrecorded. The median avoidance response obtained over the threeexperimental sessions for each rat were used for further calculations. Amedian avoidance latency>8 s was selected as an all-or-none criterionfor drug-induced inhibition of avoidance (occurring in only 1.5% ofsolvent-pretreated control rats; n=66).The results of tests 1) and 2) are shown in table 6 below.

TABLE 6 Pharmacological data for compounds according to the invention intests 1) and 2) described above. PCP means Drug-induced inhibition ofPCP-induced hyperlocomotion; CAR means Conditioned avoidance response;ED₅₀ means median effective dose; PO means oral route. Co. ED₅₀ (mg/kg)No. Route PCP CAR 6 PO 28.3 8.1* *compound 6 was in suspension in 20%hydroxypropyl-b-cyclodextrin containing 1% polysorbate 80.

3) Anticonvulsant Studies

Preparation of Test Article and Controls

Test compounds were administered using an optimal fluid volume to bodyfluid ratio. Test compounds were administered to mice in a volume of0.01 ml/g of body weight (White, H. S., et al., General principles:Experimental selection, quantification, and evaluation of antiepilepticdrugs, in Antiepileptic Drugs, Fourth Edition, R. H. Levy, R. H.Mattson, and B. S. Meldrum, Editors. 1995, Raven Press, Ltd.: New York.p. 99-110). The test compound number 6 was administered orally (p.o.).For each of the tests performed on the test compound, a 40%Hydroxypropyl-β-cyclodextrin (Hp-β-CD) stock solution was first preparedand utilized for formulating the test compound number 6 at the desiredconcentrations for testing via the oral (p.o.) route. Final compoundconcentrations were administered as suspensions in 20% Hp-β-CD. A 20%Hp-β-CD solution was used for the vehicle groups.

Critical Reagents

a) Vehicle Solutions

40% Hydroxypropyl-β-cyclodextrin (Hp-β-CD) stock solution

b) Miscellaneous Solutions

Tetracaine (0.5% solution w/v) was added dropwise from a plastic dropperbottle onto the eyes of all animals that would subsequently receiveelectrical stimulation via corneal electrodes.

Animals and Animal Husbandry

Adult male CF No 1 albino mice (26-35 g) were obtained from CharlesRiver, Portage, Mich. The animals were maintained on an adequate diet(Prolab RMH 3000) and allowed free access to food and water, exceptduring the short time they were removed from their cage for testing.Animals newly received in the laboratory were allowed sufficient time tocorrect for possible food and water restriction incurred during transitbefore being employed in testing. All mice were housed in plastic cagesin specially constructed rooms with controlled humidity, exchange of airand controlled lighting (12 hours on-12 hours off). The animals werehoused, fed, and handled in a manner consistent with the recommendationsin the National Council Publication, “Guide for the Care and Use ofLaboratory animals.”

Experimental Design General Methods Minimal Motor Impairment (MMI):

Acute MMI was assessed by a combination of direct observations of theanimal for overt symptoms of the animal's neurological or muscularfunction. In mice, the rotarod procedure was used to disclose minimalmuscular or neurological impairment. When a mouse is placed on a rodthat rotates at a speed of 6 rpm, the animal can maintain itsequilibrium for long periods of time. The animal was considered toxic ifit fell off this rotating rod three times during a 1 min period.

TPE Determination:

Groups of four animals each were administered test compounds and eachgroup was tested at one of five time points: 0.25, 0.5, 1, 2, or 4 hpost-treatment (White et al. 1995). TPE was determined using the 6 Hz(32 mA) assay. The time (0.25, 0.5, 1, 2, or 4 h post-treatment) atwhich maximal protection was observed was considered the Time of PeakEffect (TPE).

At the TPE determined for this study, or determined previously,compounds were tested in the 6 Hz assay (32 and/or 44 mA), acrossseveral doses and comprising doses that elicited little or no protectionto full protection. An ED₅₀ and 95% confidence interval (CI) werecalculated using Probit analysis on a computer program provided in thelaboratory (Finney “Probit Analysis” 34d ED 1971, London: CambridgeUniversity Press).

Serum Collection for pK/pD Analysis:

In various tests, animals were sacrificed following testing, and trunkblood and/or brain tissue (whole brains) was collected forquantification of drug levels. Immediately after testing, animals weredecapitated and trunk blood was collected into a BD Vacutainer® tubecontaining K2EDTA and chilled on ice until centrifugation. Followingcentrifugation (13000-18000 rpm, 5-7 min), the plasma was removed andtransferred to a labeled microcentrifuge tube and stored at −80° C. Forbrain tissue collection, brains were removed immediately followingdecapitation and flash frozen. The frozen sample was placed in a labeledcentrifuge tube and stored at −80° C.

6 Hz Psychomotor Seizure Test in Mice

The 6 Hz seizure test is used as a model of pharmacoresistant limbicseizures. The 6 Hz seizure displays a resistance to phenytoin,carbamazepine, lamotrigine, and topiramate (Barton et al.“Pharmacological characterization of the 6 Hz psychomotor seizure modelof partial epilepsy” Epilepsy Research 2001, Vol. 47, pp. 217-222).

Method for 6 Hz Psychomotor Seizure Test

Focal seizures were induced in mice via corneal stimulation (6 Hz, 0.2msec rectangular pulse, 3 sec duration; Barton et al. 2001). Mice weretested at either 32 mA or 44 mA. Prior to stimulation, drops of 0.5%tetracaine were applied to each eye. The seizures that arise fromcorneal stimulation in this assay are characterized by a minimal clonicphase followed by stereotyped automatistic behaviors including stun,forelimb clonus, twitching of the vibrissae, and Straub-tail. Animalsnot displaying these behaviors were considered protected.

TABLE 7 Time-to-Peak Effect Determination for Co. No. 6 (p.o.) in the 6HZ (32 mA) Assay. # rotarod motor Dose Time impairment/# (mg/kg, p.o.)(h) # protected/# tested tested 10 0.25 1/4 0/4 0.5 3/4 0/4 1 0/4 0/4 21/4 0/4 4 0/4 0/4 20 0.25 4/4 0/4 0.5 3/4 0/4 1 4/4 0/4 2 0/4 0/4 4 1/40/4 TPE determined to be 0.5 h.

TABLE 8 Dose-Response Study for Co. No. 6 in the 6 Hz Assay (32 mA and44 mA; 0.5 h TPE). # rotarod motor Dose # protected/# impairment/# Test(mg/kg, p.o.) tested tested 6 Hz 32 mA 20 7/8 0/8 10 6/8 0/8 5 2/8 0/82.5 1/8 0/8 ED₅₀ (95% CI): 7.2 mg/kg (4.2 to 11.8) 6 Hz 44 mA 40 8/8 0/820 6/8 0/8 15 4/8 0/8 10 0/8 0/8 ED₅₀ (95% CI): 16.1 mg/kg (13.0 to20.1)

Prophetic Composition Examples

“Active ingredient” as used throughout these examples relates to a finalcompound of Formula (I), the pharmaceutically acceptable salts thereof,the solvates and the stereochemically isomeric forms and the tautomersthereof. Typical examples of recipes for the formulation of theinvention are as follows:

1. Tablets

Active ingredient 5 to 50 mg Di-calcium phosphate 20 mg Lactose 30 mgTalcum 10 mg Magnesium stearate 5 mg Potato starch ad 200 mgIn this Example, active ingredient can be replaced with the same amountof any of the compounds according to the present invention, inparticular by the same amount of any of the exemplified compounds.

2. Suspension

An aqueous suspension is prepared for oral administration so that each 1milliliter contains 1 to 5 mg of one of the active compounds, 50 mg ofsodium carboxymethyl cellulose, 1 mg of sodium benzoate, 500 mg ofsorbitol and water ad 1 ml.

3. Injectable

A parenteral composition is prepared by stirring 1.5% by weight ofactive ingredient of the invention in 10% by volume propylene glycol inwater.

4. Ointment

Active ingredient 5 to 1000 mg Stearyl alcohol 3 g Lanoline 5 g Whitepetroleum 15 g Water ad 100 g

In this Example, active ingredient can be replaced with the same amountof any of the compounds according to the present invention, inparticular by the same amount of any of the exemplified compounds.

Reasonable variations are not to be regarded as a departure from thescope of the invention. It will be obvious that the thus describedinvention may be varied in many ways by those skilled in the art.

1. A compound of Formula (I)

or a stereochemically isomeric form thereof, wherein R¹ is selected fromthe group consisting of C₁₋₆alkyl, (C₃₋₈cycloalkyl)C₁₋₃alkyl, and (C₁₋₃alkyloxy)C₁₋₃alkyl; each R² is independently selected from F, Cl,C₁₋₃alkyl, C₁₋₃alkyloxy, mono- or polyhaloC₁₋₃alkyl, and mono- orpolyhaloC₁₋₃alkyloxy; n is an integer selected from 1, 2, and 3; or apharmaceutically acceptable salt or solvate thereof.
 2. The compoundaccording to claim 1, or a stereoisomeric form thereof, wherein R¹ isselected from the group consisting of CH₃CH₂, CH₃CH₂CH₂,(cyclopropyl)methyl, (cyclobutyl)methyl, ethyloxymethyl, andmethyloxymethyl; and the rest of variables are as defined in claim
 1. 3.The compound according to claim 1, wherein each R² is independentlyselected from F, Cl, CH₃, CH₃O and CF₃.
 4. The compound according toclaim 3, wherein the compound is


5. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound according to claim 1 and a pharmaceuticallyacceptable carrier or excipient.
 6. (canceled)
 7. (canceled) 8.(canceled)
 9. (canceled)
 10. (canceled)
 11. A method of treating orpreventing a central nervous system disorder selected from the group ofanxiety disorders, psychotic disorders selected from the groupconsisting of schizophrenia, schizoaffective disorder andschizophreniform disorder, personality disorders, substance-relateddisorders, eating disorders, mood disorders, migraine, epilepsy orconvulsive disorders, childhood disorders, cognitive disorders,neurodegeneration, autistic disorders, neurotoxicity and ischemiacomprising administering to a subject in need thereof, a therapeuticallyeffective amount of a compound according to claim
 1. 12. The methodaccording to claim 11, wherein the psychotic disorders are selected fromthe group of schizophrenia, schizoaffective disorder andschizophreniform disorder; the anxiety disorders are selected from thegroup of agoraphobia, generalized anxiety disorder (GAD), mixed anxietyand depression, obsessive-compulsive disorder (OCD), panic disorder,posttraumatic stress disorder (PTSD), social phobia and other phobias;the personality disorders are selected from the group ofobsessive-compulsive personality disorder, borderline personalitydisorder and schizoid, schizotypal disorder; the substance abuse orsubstance-related disorders are selected from the group of alcoholabuse, alcohol addiction, alcohol dependence, alcohol withdrawal,alcohol withdrawal delirium, alcohol-induced psychotic disorder,amphetamine addiction, amphetamine dependence, amphetamine withdrawal,cocaine addiction, cocaine dependence, cocaine withdrawal, nicotineaddiction, nicotine dependence, nicotine withdrawal, opioid dependenceand opioid withdrawal; the eating disorders are selected from the groupof anorexia nervosa and bulimia nervosa; the mood disorders are selectedfrom the group of bipolar disorders (I & II), cyclothymic disorder,depression, dysthymic disorder, major depressive disorder, treatmentresistant depression, bipolar depression, and substance-induced mooddisorder; the epilepsy or convulsive disorders are selected from thegroup of generalized nonconvulsive epilepsy, generalized convulsiveepilepsy, petit mal status epilepticus, grand mal status epilepticus,partial epilepsy with or without impairment of consciousness, infantilespasms, epilepsy partialis continua, and other forms of epilepsy; thecognitive disorders are selected from the group of delirium,substance-induced persisting delirium, dementia, dementia due to HIVdisease, dementia due to Huntington's disease, dementia due toParkinson's disease, dementia of the Alzheimer's type, behavioral andpsychological symptoms of dementia, substance-induced persistingdementia and mild cognitive impairment; the autistic disorders areselected from autism and autism spectrum disorders, such as Asperger'ssyndrome.
 13. A method of treating or preventing a central nervoussystem disorder selected from the group of anxiety disorders selectedfrom the group of agoraphobia, generalized anxiety disorder, panicdisorder, social anxiety disorder (social phobia), and panic attack;schizophrenia spectrum and other psychotic disorders selected from thegroup of schizophrenia, schizoaffective disorder and schizophreniformdisorder; personality disorders selected from the group ofobsessive-compulsive personality disorder, borderline personalitydisorder, schizoid personality disorder, and schizotypal personalitydisorder; substance-related and addictive disorders selected from thegroup of alcohol use disorder, alcohol withdrawal, opioid use disorder,opioid withdrawal, stimulant (amphetamine-type substance, cocaine) usedisorder, stimulant (amphetamine-type substance, cocaine) withdrawal,tobacco use disorder, and tobacco withdrawal; depressive disordersselected from the group of major depressive disorder, persistentdepressive disorder (dysthymia), and substance/medication-induceddepressive disorder; bipolar and related disorders selected from thegroup of bipolar I disorder, bipolar II disorder, cyclothymic disorder,substance/medication-induced bipolar and related disorder;obsessive-compulsive disorder; trauma- and stressor-related disordersselected from the group of posttraumatic stress disorder, and acutestress disorder; neurodevelopmental disorders selected from the group ofautism spectrum disorder, and attention-deficit/hyperactivity disorder;neurocognitive disorders (NCDs) (both major and mild) selected from thegroup of delirium, substance intoxication delirium, NCD due toAlzheimer's disease, NCD due to HIV infection, NCD due to Huntington'sdisease, NCD due to Parkinson's disease, andsubstance/medication-induced NCD; and epilepsy or convulsive disordersselected from the group of generalized nonconvulsive epilepsy,generalized convulsive epilepsy, petit mal status epilepticus, grand malstatus epilepticus, partial epilepsy with or without impairment ofconsciousness, infantile spasms, epilepsy partialis continua, and otherforms of epilepsy. comprising administering to a subject in needthereof, a therapeutically effective amount of a compound according toclaim
 1. 14. The method according to claim 12, wherein the centralnervous system disorder is selected from the group of schizophrenia (inparticular, negative symptoms or residual symptoms thereof), generalizedanxiety disorder, bipolar disorder (I or II), migraine, behavioral andpsychological symptoms of dementia, epilepsy or convulsive disorders,panic disorder, mixed anxiety and depression, and agoraphobia.
 15. Aproduct comprising (a) a compound as defined in claim 1; and (b) anmGluR2 orthosteric agonist, as a combined preparation for simultaneous,separate or sequential use in the treatment or prevention of a centralnervous system disorder selected from the group of schizophrenia (inparticular, negative symptoms or residual symptoms thereof), generalizedanxiety disorder, bipolar disorder (I or II), migraine, behavioral andpsychological symptoms of dementia, epilepsy or convulsive disorders,panic disorder, mixed anxiety and depression, and agoraphobia.